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Stem Cells Market to Inspire a Growth up to US$ 18289.9 Million at a 9.1% CAGR by 2027 – PharmiWeb.com

By daniellenierenberg

Stem cells are undifferentiated cells which are capable of differentiating into any type of cell that make-up the human body and thus, are capable of producing non-regenerative cells such as neural and myocardial cells.

Statistics:

The global stem cells market is estimated to account forUS$ 9,941.2 Mnin terms of value in2020and is expected to reachUS$ 18,289.9 Mnby the end of2027.

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GlobalStem CellsMarket: Drivers

Approval and launch of new products is expected to propel growth of the global stem cells market over the forecast period. For instance, in December 2019, BioRestorative Therapies, Inc. received a Notice of Allowance on its patent application for a method of generating brown fat stem cells from Israeli Patent Office.

Moreover, increasing number of stem cell banking resource centers is also expected to aid in growth of the market. For instance, in March 2020, Stemlife Berhad, a cord blood bank in Malaysia, started a Stem Cell Banking Resource Center in Jerudong Park Medical Center, Brunei.

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Statistics:

Adult stem cells held dominant position in the global stem cells market in 2019, accounting for81.2%share in terms of value, followed by Human Embryonic Stem Cells and Induced Pluripotent Stem Cells, respectively

Figure 1. GlobalStem CellsMarket Share (%), by Value, by Cell Type, 2019.

GlobalStem CellsMarket: Restraints

High cost of stem cell therapy is expected to hinder growth of the global stem cells market. For instance, Bioinformant a research firm engaged in stem cell research, reported that the cost of stem cell therapy ranges between US$ 5,000-8,000 per patient and in some cases it may rise as much as US$ 25,000 or more depending on the complexity of the procedure.

Moreover, restrictions on research activities related to stem cells had hampered the growth of embryonic stem cells historically and resulted in its meager share in the total market in spite of its advantages over adult stem cells.

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GlobalStem CellsMarket: Opportunities

R&D in stem cell donation is expected to offer lucrative growth opportunities for players in the global stem cells market. For instance, in March 2020, researchers from Dankook University and Catholic University, South Korea, reported investigation of the types and degrees of physical and psychological discomfort experienced by hematopoietic stem cell donors before, during, and after the donation process.

Moreover, adoption of online distribution channel is also expected to aid in growth of the global stem cells market. For instance, The US Direct-to-Consumer Marketplace for Autologous Stem Cell Interventions, published in the journal Perspectives in Biology and Medicine, in 2018, the number of new stem cell businesses with websites doubled on average every year between 2009 and 2014, in the U.S.

The global stem cells market was valued atUS$ 9,112.0 Mnin2019and is forecast to reach a value ofUS$ 18,289.9 Mnby2027at aCAGR of 9.1%between2020 and 2027.

Figure 2. GlobalStem CellsMarket Value (US$ Mn), and Y-o-Y Growth (%), 2019-2027

Market Trends/Key Takeaways

Adoption of stem cells for the treatment of various diseases is expected to propel growth of the global stem cells market. For instance, in January 2020, researchers at University of Houston developed biologic cardiac pacemaker-like cells by taking fat stem cells and reprogramming them as an alternative treatment for heart conditions such as conduction system disorders and heart attacks.

Moreover, increasing investment in stem cell therapies is also expected to aid in growth of the market. For instance, in July 2018, the Emory Orthopaedics & Spine Center, in collaboration with Sanford Health, Duke University, Andrews Institute, and Georgia Institute of Technology, received US$ 13 million grant from the Marcus Foundation for a multicenter clinical trial studying stem cell options for treating osteoarthritis. The Phase 3 trial was initiated in March 2019, and is expected to complete by December 2021.

GlobalStem CellsMarket: Competitive Landscape

Major players operating in the global stem cells market include Advanced Cell Technology, Inc., Angel Biotechnology Holdings PLC, Bioheart Inc., Lineage Cell Therapeutics., BrainStorm Cell Therapeutics, Inc., California Stem Cell Inc., Celgene Corporation, Takara Bio Europe AB, Cellular Engineering Technologies, Cytori Therapeutics Inc., Osiris Therapeutics, and STEMCELL Technologies Inc.

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GlobalStem CellsMarket: Key Developments

Major players in the market are focused on adopting collaboration and partnership strategies to expand their product portfolio. For instance, in September 2018, STEMCELL Technologies signed an exclusive license agreement with Brigham and Womens Hospital for rights to commercialize technologies for the generation of human pluripotent stem cell-derived kidney organoids.

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The Untapped Potential of Cell and Gene Therapy – AJMC.com Managed Markets Network

By daniellenierenberg

We can absolutely cut the number of cancer deaths down so that one day in our lifetimes it can be a rare thing for people to die of cancer, said Patrick Hwu, MD, president and CEO of Moffitt Cancer Center in Florida and among gene therapys pioneers. It still may happen here and there, but itll be kind of like people dying of pneumonia. Its like, He died of pneumonia? Thats kind of weird. I think cancer can be the same way.

The excitement returned in spades in 2017 when the FDA signed off on a gene-therapy drug for the first time, approving the chimeric antigen receptor (CAR) T-cell treatment tisagenlecleucel (Kymriah; Novartis) for the treatment of B-cell precursor acute lymphoblastic leukemia. At last, scientists had devised a way to reprogram a persons own T cells to attack tumor cells.

Were entering a new frontier, said Scott Gottlieb, MD, then the FDA Commissioner, in announcing the groundbreaking approval.

Gottlieb wasnt exaggerating. The growth in CAR T-cell treatments is exploding. Although only a handful of cell and gene therapies are on the market, FDA officials predicted in 2019 that the agency will receive more than 200 investigational new drug applications per year for cell and gene therapies, and that by 2025, it expects to have accelerated to 10 to 20 cell and gene therapy approvals per year.1

Essentially, you can kill any cancer cell that has an antigen that is recognized by the immune cell, Hwu said. The key to curing every single cancer, which is our goal, is to have receptors that can recognize the tumor but dont recognize the normal cells. Receptors recognizing and then attacking normal cells is what can cause toxicity.

Cell therapy involves cultivating or modifying immune cells outside the body before injecting them into the patient. Cells may be autologous (self-provided) or allogeneic (donor-provided); they include hematopoietic stem cells and adult and embryonic stem cells. Gene therapy modifies or manipulates cell expression. There is considerable overlap between the 2 disciplines.

Juliette Hordeaux, PhD, senior director of translational research for the University of Pennsylvanias gene therapy program, is cautious about the FDAs predictions, saying shed be thrilled with 5 cell and/or gene therapy approvals annually.

For monogenic diseases, there are only a certain number of mutations, and then well plateau until we reach a stage where we can go after more common diseases, Hordeaux said.

Safety has been the main brake around adeno-associated virus vector (AAV) gene therapy, added Hordeaux, whose hospitals program has the institutional memory of both Jesse Gelsingers tragic death during a 1999 gene therapy trial as well as breakthroughs by Carl June, MD, and others in CAR T-cell therapy.

Sometimes there are unexpected toxicity [events] in trials.I think figuring out ways to make gene therapy safer is going to be the next goal for the field before we can even envision many more drugs approved.

In total, 3 CAR T-cell therapies are now on the market, all targeting the CD19 antigen. Tisagenlecleucel was the first. Gilead Sciences received approval in October 2017 for axicabtagene ciloleucel (axi-cel; Yescarta), a CAR T-cell therapy for adults with large B-cell non-Hodgkin lymphoma. Kite Pharma, a subsidiary of Gilead, received an accelerated approval in July 2020 for brexucabtagene autoleucel (Tecartus) for adults with relapsed or refractory mantle cell lymphoma.

On February 5, 2021, the FDA approved another CD19-directed therapy for relapsed/refractory large B-cell lymphoma, lisocabtagene maraleucel (liso-cel; JCAR017; Bristol Myers Squibb). The original approval date was missed due to a delay in inspecting a manufacturing facility (see related article).

Idecabtagene vicleucel (ide-cel; bb2121; Bristol Myers Squibb) is under priority FDA review, with a decision expected by March 31, 2021. The biologics license application seeks approval for ide-cel, a B-cell maturation antigendirected CAR therapy, to treat adult patients with multiple myeloma who have received at least 3 prior therapies.2

The number of clinical trials evaluating CAR T-cell therapies has risen sharply since 2015, when investigators counted a total of 78 studies registered on the ClinicalTrials.gov website. In June 2020, the site listed 671 trials, including 357 registered in China, 256 in the United States, and 58 in other countries.3

Natural killer (NK) cells are the research focus of Dean Lee, MD, PhD, a physician in the Division of Hematology and Oncology at Nationwide Childrens Hospital. He developed a method for consistent, robust expansion of highly active clinical-grade NK cells that enables repeated delivery of large cell doses for improved efficacy. This finding led to several first-in-human clinical trials evaluating adoptive immunotherapy with expanded NK cells under an FDA Investigational New Drug application. He is developing both genetic and nongenetic methods to improve tumor targeting and tissue homing of NK cells. His eff orts are geared toward pediatric sarcomas.

The biggest emphasis over the past 20 to 25 years has been cell therapy for cancer, talking about trying to transfer a specific part of the immune system for cells, said Lee, who is also director of the Cellular Therapy and Cancer Immunology Program at Nationwide Childrens Hospital, at The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital, and at the Richard J. Solove Research Institute.

The Pivot Toward Treating COVID-19 and Other Diseases

However, Lee said, NKs have wider potential. This is kind of a natural swing back. Now that we know we can grow them, we can reengineer them against infectious disease targets and use them in that [space], he said.

Lee is part of a coronavirus disease 2019 (COVID-19) clinical trial, partnering with Kiadis, for off-the-shelf K-NK cells using Kiadis proprietary platforms. Such treatment would be a postexposure preemptive therapy for treating COVID-19. Lee said the pivot toward treating COVID-19 with cell therapy was because some of the very early reports on immune responses to coronavirus, both original [SARS-CoV-2] and the new [mutation], seem to implicate that those who did poorly [overall] had poorly functioning NK cells.

The revolutionary gene editing tool CRISPR is making its initial impact in clinical trials outside the cancer area. Its developers, Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD, won the Nobel Prize in Chemistry 2020.

For patients with sickle cell disease (SCD), CRISPR was used to reengineer bone marrow cells to produce fetal hemoglobin, with the hope that the protein would turn deformed red blood cells into healthy ones. National Public Radio did a story on one patient who, so far, thanks to CRISPR, has been liberated from the attacks of SCD that typically have sent her to the hospital, as well from the need for blood transfusions.4

Its a miracle, you know? the patient, Victoria Gray of Forest, Mississippi, told NPR.

She was among 10 patients with SCD or transfusion-dependent beta-thalassemia treated with promising results, as reported by the New England Journal of Medicine.5 Two different groups, one based in Nashville, which treated Gray,5 and another based at Dana-Farber Cancer Institute in Boston,6 have reported on this technology.

Stephen Gottschalk, MD, chair of the department of bone marrow transplantation and cellular therapy at St Jude Childrens Research Hospital, said, Theres a lot of activity to really explore these therapies with diseases that are much more common than cancer.

Animal models use T cells to reverse cardiac fibrosis, for instance, Gottschalk said. Using T cells to reverse pathologies associated with senescence, such as conditions associated with inflammatory clots, are also being studied.

Hordeaux said she foresees AAV being used more widely to transmit neurons to attack neurodegenerative diseases.

The neurons are easily transduced by AAV naturally, she said. AAV naturally goes into neurons very efficiently, and neurons are long lived. Once we inject genetic matter, its good for life, because you dont renew neurons.

Logistical Issues

Speed is of the essence, as delays in producing therapies can be the difference between life and death, but the approval process takes time. The process of working out all kinks in manufacturing also remains a challenge. Rapid production is difficult, too, because of the necessary customization of doses and the need to ensure a safe and effective transfer of cells from the patient to the manufacturing center and back into the patient.7

Other factors that can slow down launches include insurance coverage, site certification, staff training, reimbursement, and patient identification. The question of how to reimburse has not been definitively answered; at this point, insurers are being asked to issue 6- or even 7-figure payments for treatments and therapies that may not work.8

CAR T, I think, will become part of the standard of care, Gottschalk said. The question is how to best get that accomplished. To address the tribulations of some autologous products, a lot of groups are working with off -the-shelf products to get around some of the manufacturing bottlenecks. I believe those issues will be solved in the long run.

References

1. Statement from FDA Commissioner Scott Gottlieb, MD, and Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies. News release. FDA website. January 15, 2019. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics. Accessed January 13, 2021.

2. Bristol Myers Squibb provides regulatory update on lisocabtagene maraleucel (liso-cel). News release. Bristol Myers Squibb; November 16, 2020. Accessed January 11, 2021. https://news.bms.com/news/details/2020/Bristol-Myers-Squibb-Provides-Regulatory-Update-on-Lisocabtagene-Maraleucel-liso-cel/default.aspx

3. Wei J, Guo Y, Wang Y. et al. Clinical development of CAR T cell therapy in China: 2020 update. Cell Mol Immunol. Published online September 30, 2020. doi:10.1038/s41423-020-00555-x

4. Stein R. CRISPR for sickle cell diseases shows promise in early test. Public Radio East. November 19, 2019. Accessed January 11, 2021. https://www.publicradioeast.org/post/crisprsickle-cell-disease-shows-promise-early-test

5. Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and -Thalassemia. N Engl J Med. Published online December 5, 2020. DOI: 10.1056/NEJMoa2031054

6. Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. Published online December 5, 2020. doi:10.1056/NEJMoa2029392

7. Yednak C. The gene therapy race. PwC. February 5, 2020. Accessed January 11, 2021. https://www.pwc.com/us/en/industries/healthindustries/library/gene-therapy-race.html

8. Gene therapies require advanced capabilities to succeed after approval. PwC website. Accessed January 11, 2021. https://www.pwc.com/us/en/industries/health-industries/library/commercializing-gene-therapies.html

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Grayson-Jockey Club Research Foundation Board approves record funding for Equine Research – Past The Wire

By daniellenierenberg

LEXINGTON, Ky. Board of directors of Grayson-Jockey Club Research Foundation announced today that it has authorized expenditure of $1,638,434, the most that the foundation has ever allocated in a year, to fund 12 new projects at 12 universities, 12 continuing projects, and two career development awards worth $20,000 each. This marks the seventh straight year that more than $1 million has been approved. The 2021 slate of research brings Grayson-Jockey Club Research Foundations totals since 1983 to more than $30.6million to underwrite 396 projects at 45 universities.

We are heartened by the continued commitment of universities to supporting equine veterinary research throughout these difficult times and that we are able to distribute more funding than ever before, enabling us to help horses of all breeds and disciplines, said Dell Hancock, chair of Grayson.

Despite a challenging year, Grayson-Jockey Club was excited to receive 51 grant applications from a variety of veterinary institutions in North America as well as five other countries, said Dr. Stephen M. Reed, chair of Graysons research advisory committee. The subject matter is diverse and ranges from identifying new methods to treat and prevent infectious disease to development of computational models using big data to investigation of novel imaging techniques to prevent orthopedic injuries.

Below is an alphabetical list by school of the new projects:

Passive Immunization of Foals with RNA-AB against R Equi

Jeroen Pollet, Baylor College of Medicine

By inhalation therapy, we intend to deliver the genetic code for a protective antibody against Rhodococcus equi into the lung cells of newborn foals, to rapidly protect them against infection.

Hyperthermia and Acidosis in Exertional Muscle Damage

Michael Davis,Oklahoma State University

This project will identify an underlying cause of exercise-associated muscle fatigue and soreness and allow trainers to more precisely condition horses with fewer training days lost to muscle soreness.

Developing an Improved Serological Test for Strangles

Noah Cohen, Texas A&M

We propose to develop a more accurate blood test to identify horses infected with the bacterium that causes strangles to improve control and prevention of strangles.

Mitigation of Equine Recurrent Uveitis through SOCS

Joseph Larkin, University of Florida

We seek to design a topical eye drop, using a natural protein, which helps to prevent pain and blindness associated with equine recurrent uveitis.

Environmental Origins of Equine Antimicrobial Resistance

Brandy Burgess, University of Georgia

This study will elucidate how antimicrobial resistance and virulence determinants are shared among horses and hospital environment, as well as the role antimicrobial exposure plays at this interface.

Treatment of Joint Injury with Mesenchymal Stromal Cells

Thomas Koch, University of Guelph

Evaluation of equine umbilical cord blood-derived mesenchymal stromal cells to treat joint injuries in horses.

Optimizing Bone Growth to Reduce Equine Fracture

Mariana Kersh, University of Illinois UrbanaChampaign

Reduction in distal limb fractures through exercise in young horses would have a significant positive impact on horse welfare and the economics and public perception of the horse industry.

New Generation Equine Influenza Bivalent VLP Vaccine

Thomas Chambers, University of Kentucky

We propose to create a novel, safe and effective vaccine for equine influenza based on the 21st-century technology of noninfectious virus-like particles produced in plants.

Injury Prediction from Stride Derived Racing Load

Chris Whitton, University of Melbourne

By studying patterns in bone fatigue accrual over time in racehorses, we will better, and earlier, identify horses at risk of limb injury, facilitating timely evidence based preventative strategies.

Predicting Exercising Arrhythmias with Resting ECGs

Molly McCue, University of Minnesota

We will use at rest ECGs to identify horses with irregular heart rhythms at exercise that can cause sudden cardiac death (SCD), allowing for increased monitoring and improved understanding of SCD.

Understanding and Preventing Supporting Limb Laminitis

Andrew Van Eps,University of Pennsylvania

We aim to make supporting limb laminitis preventable through analysis of archived model tissues, a multi-center limb motion study of horses at risk, and development of a prototype therapeutic device.

Diagnosis of Incipient Condylar Stress Fracture

Peter Muir,University of Wisconsin-Madison

This study will save the lives of racehorses by establishing screening using fetlock CT for diagnosis of horses with a high risk of imminent serious injury for personalized clinical care.

The Storm Cat Career Development Award, inaugurated in 2006, grants $20,000 to an individual considering a career in equine research.This years recipient is Dr. Callum G. Donelly of the University of California, Davis. Dr. Donelly has completed his residency program and is in a research training position under the mentorship of Dr. Carrie Fino. His project, Proteomic Investigation of Equine Spinal Ataxia, is expected to identify novel protein biomarkers that differentiate normal horses from those with spinal ataxia, with high sensitivity and specificity.

The Elaine and Bertram Klein Career Development Award was first awarded in 2015 and grants $20,000 to a prospective equine researcher. This years recipient is Dr. Aileen Rowland of Texas A&M University. Dr. Rowlands research focuses on the efficacy of xenogeny-free mesenchymal stem cells for osteoarthritis.

We are pleased to continue our funding of two career development awards to support individuals passionate about equine research, said Dr. Johnny Mac Smith, consultant to the research advisory committee. Dr. Donelly and Dr. Rowland are worthy recipients of these grants, and I look forward to seeing how their current and future projects contribute to improving equine health in the future.

Details on the new projects are available at the following link:grayson-jockeyclub.org/default.asp?section=2&area=Research&menu=2.

Grayson-Jockey Club Research Foundation is traditionally the nations leading source of equine research funding. The projects it supports enhance the health and safety of horses of all breeds. Additional information about the foundation is available atgrayson.jockeyclub.org.

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Astellas and Seagen Announce Submission of Two Supplemental Biologics License Applications to the US FDA for PADCEV (enfortumab vedotin-ejfv) in…

By daniellenierenberg

TOKYOand BOTHELL, Wash., Feb. 18, 2021 /PRNewswire/ --Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq:SGEN) today announced completion of submissions for two supplemental Biologics License Applications (sBLAs) to the U.S. Food and Drug Administration (FDA) for PADCEV (enfortumab vedotin-ejfv). One submission, based on the phase 3 EV-301 trial, seeks to convert PADCEV's accelerated approval to regular approval. The second submission, based on the pivotal trial EV-201's second cohort, requests an expansion of the current label to include patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor and are ineligible for cisplatin.

The FDA is reviewing both applications under the Real-Time Oncology Review (RTOR) pilot program. The RTOR program aims to explore a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible.

"The FDA's review of our applications under Real-Time Oncology Review supports our efforts to expand PADCEV's availability as a treatment option for more patients as quickly as possible," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas. "Locally advanced or metastatic urothelial cancer is an aggressive disease with limited treatment options."

The sBLA for regular approval of PADCEV in the U.S. is supported by data from the global EV-301 phase 3 confirmatory trial, which compared PADCEV to chemotherapy in adult patients with locally advanced or metastatic urothelial cancer who were previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor. The trial's primary endpoint was overall survival of patients treated with PADCEV vs. chemotherapy, and full results were presented at the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) and published in the New England Journal of Medicine.[1]

The second submission, for a label expansion in the U.S., is based on results from the second cohort of EV-201, a pivotal phase 2 clinical trial evaluating PADCEV in patients with locally advanced or metastatic urothelial cancer who had received prior immunotherapy treatment but were not eligible for cisplatin. The trial's primary endpoint was objective response rate, and full results were presented at ASCO GU.[2]

"Advanced bladder cancer patients urgently need more treatment options," said Roger Dansey, M.D., Chief Medical Officer, Seagen. "Based on recently presented clinical trial results, PADCEV could address a significant unmet need for more patients with advanced urothelial cancer after initial immunotherapy treatment."

In 2019 PADCEV received accelerated approval in the U.S. for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/L1 inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery in a locally advanced or metastatic urothelial cancer setting. PADCEV is currently only approved for use in the U.S.

About the EV-301 TrialThe EV-301 trial (NCT03474107) is a global, multicenter, open-label, randomized phase 3 trial designed to evaluate enfortumab vedotin versus physician's choice of chemotherapy (docetaxel, paclitaxel or vinflunine) in approximately 600 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/L1 inhibitor and platinum-based therapies. The primary endpoint is overall survival and secondary endpoints include progression-free survival, overall response rate, duration of response and disease control rate, as well as assessment of safety/tolerability and quality-of-life parameters.

About the EV-201 TrialThe EV-201 trial (NCT03219333) is a single-arm, dual-cohort, pivotal phase 2 clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy in this setting and who are ineligible for cisplatin (cohort 2). The trial enrolled 128 patients in cohort 1 and 91 patients in cohort 2 at multiple centers internationally. The primary endpoint is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety and tolerability.

About Urothelial CancerUrothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.[3] Globally, approximately 549,000 new cases of bladder cancer and 200,000 deaths are reported annually.[4]

About PADCEV (enfortumab vedotin-ejfv)PADCEV was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA's Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.[5]

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.5,[6] Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).5 PADCEV is co-developed by Astellas and Seagen.

PADCEV Important Safety Information

Warnings and Precautions

Adverse ReactionsSerious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab AbnormalitiesIn one clinical trial, Grade 3-4 laboratory abnormalities reported in 5% were: lymphocytes decreased (10%), hemoglobin decreased (10%), phosphate decreased (10%), lipase increased (9%), sodium decreased (8%), glucose increased (8%), urate increased (7%), neutrophils decreased (5%).

Drug Interactions

Specific Populations

For more information, please see the full Prescribing Information for PADCEV here.

About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+ healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website athttps://www.astellas.com/en.

About Seagen Seagen Inc. is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people's lives. Seagen is headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland and the European Union. For more information on our marketed products and robust pipeline, visit http://www.seagen.com and follow @SeagenGlobal on Twitter.

About the Astellas and Seagen CollaborationAstellas and Seagen are co-developing enfortumab vedotin under a collaboration that was entered into in 2007 and expanded in 2009.

Astellas Cautionary NotesIn this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development), which is included in this press release is not intended to constitute an advertisement or medical advice.

Seagen Forward Looking StatementsCertain statements made in this press release are forward looking, such as those, among others, relating to the potential conversion of PADCEV's current accelerated approval in the U.S. to regular approval and the potential expansion of the current PADCEV label to include patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor and are ineligible for cisplatin, and the therapeutic potential of PADCEV, including its efficacy, safety and therapeutic uses. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include, without limitation, the possibility that the sBLA submissions based on the EV-301 and EV-201 second cohort clinical trials may not be accepted for filing by, or ultimately approved by, the FDA in a timely manner or at all; that the results of the EV-301 clinical trial may not be sufficient to convert PADCEV's accelerated approval in the U.S. to regular approval and that the results of the second cohort of the EV-201 clinical trial may not be sufficient to support the requested label expansion; that, even if PADCEV receives regular approval and even if the PADCEV label is expanded based on the results of the second cohort of the EV-201 clinical trial, the product labeling may not be as broad or desirable as requested or anticipated; and that setbacks in the development and commercialization of PADCEV could occur as a result of the difficulty and uncertainty of pharmaceutical product development, the risk of adverse events or safety signals, the failure of ongoing and subsequent clinical trials to establish sufficient efficacy, or as a result of adverse regulatory actions. More information about the risks and uncertainties faced by Seagen is contained under the caption "Risk Factors" included in the company's Annual Report on Form 10-K for the year ended December 31, 2020 filed with the Securities and Exchange Commission. Seagen disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

[1]Powles T, Rosenberg J, Sonpavde G, et al. Primary Results of EV-301: A Phase 3 Trial of Enfortumab Vedotin vs Chemotherapy in Patients With Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma. ASCO Meeting Library 2021. https://meetinglibrary.asco.org/record/194738/abstract. Accessed February 11, 2021.[2] Balar AV, McGregor B, Rosenberg J, et al. EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. ASCO Meeting Library 2021. https://meetinglibrary.asco.org/record/194731/abstract. Accessed February 11, 2021.[3]American Society of Clinical Oncology. Bladder cancer: introduction (5-2019). https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed January 27, 2021.[4]Cancer today: data visualization tools for exploring the global cancer burden in 2020. https://gco.iarc.fr/today/home. Accessed January 27, 2021.[5]PADCEV [package insert] Northbrook, IL: Astellas Pharma Inc.[6]Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res 2016;76(10):3003-13.

SOURCE Astellas Pharma Inc.

http://www.us.astellas.com

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Astellas and Seagen Announce Submission of Two Supplemental Biologics License Applications to the US FDA for PADCEV (enfortumab vedotin-ejfv) in...

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[Full text] A Comprehensive Review on Factors Influences Biogenesis, Functions, Th | IJN – Dove Medical Press

By daniellenierenberg

Introduction

Extracellular vesicles (EVs) including exosomes, microvesicles, and apoptotic bodies are produced and released by almost all types of cell. EVs vary in size, properties, and secretion pathway depending on the originating cell.1,2 Exosomes are small EVs (sEVs) which are formed by a process of inward budding in early endosomes to form multivesicular bodies (MVBs) with an average size of 100 nm, and released into the extracellular microenvironment to transfer their components.3,4 Microvesicles are composed of lipid components of the plasma membrane and their sizes range from 1001000 nm, whereas apoptotic bodies result from programmed cell death.5 Initially, EVs were considered to maintain cellular waste through release of unwanted proteins and biomolecules; later, these organelles were considered important for intercellular communications through various cargo molecules such as lipids, proteins, DNA, RNA, and microRNAs (miRNAs).6 Previously, it was suggested that EVs play a critical role in normal cells to maintain homeostasis and prevent cancer initiation. Inhibition of EVs secretion causes accumulation of nuclear DNA in the cytoplasm, leading to apoptosis.1 The induction of apoptosis is the principal event of the reactive oxygen species (ROS) dependent DNA damage response.7,8

Several studies reported that exosomes are synthesized by means of two major pathways, the endosomal sorting complexes required for transport (ESCRT)-dependent and ESCRT-independent, and the processes are highly regulated by multiple signal transduction cascades.18 Exosomes released from the cell through normal exocytosis mechanisms are characterized by vesicular docking and fusion with the aid of SNARE complexes. Exosomes are considered to be organelle responsible for garbage disposal agents. However, at a later stage, these secretory bodies play a critical role in maintaining the physiological and pathological conditions of the surrounding cells by transferring information from donor cells to recipient cells. Exosome development begins with endocytosis to form early endosomes, later forming multivesicular endosomes (MVEs), and finally generating late endosomes by inward budding. MVEs merge with the cell membrane and release intraluminal endosomal vesicles that become exosomes into the extracellular space.9,10 Exosome biogenesis is dependent on various critical factors including the site of biogenesis, protein sorting, physicochemical aspects, and transacting mediators.11

Exosomes contain various types of cargo molecules including lipids, proteins, DNAs, mRNAs, and miRNAs. Most of the cargo is involved in the biogenesis and transportation ability of exosomes.12,13 Exosomes are released by fusion of MVBs with the cell membrane via activation of Rab-GTPases and SNAREs. Exosomes are abundant and can be isolated from a wide variety of body fluids and also cell culture medium.14 Exosomes contain tetraspanins that are responsible for cell penetration, invasion, and fusion events. Exosomes are released onto the external surface by the MVB formation proteins Alix and TSG101. Exosome-bound proteins, annexins and Rab protein, govern membrane transport and fusion whereas Alix, flotillin, and TSG101 are involved in exosome biogenesis.15,16 Exosomes contain various types of proteins such as integral exosomal membrane proteins, lipid-anchored outer and inner membrane proteins, peripheral surface and inner membrane proteins, exosomal enzymes, and soluble proteins that play critical roles in exosome functions.11

The functions of exosomes depend on the origin of the cell/tissue, and are involved in the immune response, antigen presentation programmed cell death, angiogenesis, inflammation, coagulation, and morphogen transporters in the creation of polarity during development and differentiation.1720 Ferguson and Nguyen reported that the unique functions of exosomes depend on the availability of unique and specific proteins and also the type of cell.21 All of these categories influence cellular aspects of proteins such as the cell junction, chaperones, the cytoskeleton, membrane trafficking, structure, and transmembrane receptor/regulatory adaptor proteins. The role of exosomes has been explored in different pathophysiological conditions including metabolic diseases. Exosomes are extremely useful in cancer biology for the early detection of cancer, which could increase prognosis and survival. For example, the presence of CD24, EDIL3, and fibronectin proteins on circulating exosomes has been proposed as a marker of early-stage breast cancer.22 Cancer-derived exosomes promoted tumor growth by directly activating the signaling pathways such as P13K/AKT or MAPK/ERK.23 Tumor-derived exosomes are significantly involved in the immune system, particularly stimulating the immune response against cancer and delivering tumor antigens to dendric cells to produce exosomes, which in turn stimulates the T-cell-mediated antitumor immune response.24 Exosomal surface proteins are involved in immunotherapies through the regulation of the tumor immune microenvironment by aberrant cancer signaling.25 A study demonstrated that exosomes have the potential to affect health and pathology of cells through contents of the vesicle.26 Exosomes derived from mesenchymal stem cells exhibit protective effects in stroke models following neural injury resulting from middle cerebral artery occlusion.27 The structural region of the exosome facilitate the release of misfolded and prion proteins, and are also involved in the propagation of neurodegenerative diseases such as Huntington disease, Alzheimers disease (AD), and Parkinsons disease (PD).28,29

Exosomes serve as novel intercellular communicators due to their cell-specific cargo of proteins, lipids, and nucleic acids. In addition, exosomes released from parental cells may interact with target cells, and it can influence cell behavior and phenotype features30 and also it mediate the horizontal transfer of genetic material via interaction of surface adhesion proteins.31 Exosomes are potentially serving as biomarkers due to the wide-spread and cell-specific availability of exosomes in almost all body fluids.13 Therefore, exosomes are exhibited as delivery vehicles for the efficient delivery of biological therapeutics across different biological barriers to target cells.3234

In this review, first, we comprehensively describe the factors involved in exosome biogenesis and the role of exosomes in intercellular signaling and cell-cell communications, immune responses, cellular homeostasis, autophagy, and infectious diseases. In addition, we discuss the role of exosomes as diagnostic markers, and the therapeutic and clinical implications. Finally, we discuss the challenges and outstanding developments in exosome research.

The extracellular vesicles play critical role in inter cellular communication by serving as vehicles for transfer of biomolecules. These vesicles are generally classified into microvesicles, ectosomes, shedding vesicles, or microparticles. MVs bud directly from the plasma membrane, whereas exosomes are represented by small vesicles of different sizes that are formed as the ILV by budding into early endosomes and MVBs and are released by fusion of MVBs with the plasma membrane (Figure 1). Invagination of late endosomal membranes results in the formation of intraluminal vesicles (ILVs) within large MVBs.35 Biogenesis of exosomes occurs in three ways including vesicle budding into discrete endosomes that mature into multivesicular bodies, which release exosomes upon plasma membrane fusion; direct vesicle budding from the plasma membrane; and delayed release by budding at intracellular plasma membrane-connected compartments (IPMCs) followed by deconstruction of IPMC neck(s).11 The mechanisms of biogenesis of exosomes are governed by various types of proteins including the ESCRT proteins Hrs, CHMP4, TSG101, STAM1, VPS4, and other proteins such as the Syndecan-syntenin-ALIX complex, nSMase2, PLD2, and CD9.14,3639 After formation, the MVB can either fuse with the lysosome to degrade its content or fuse with the plasma membrane to release the ILVs as exosomes. The release of exosomes to the extracellular milieu is driven by proteins of the Rab-GTPase family including RAB2B, 5A, 7, 9A, 11, 27, and 35. SNARE family proteins VAMP7 and YKT6 have also been implicated in the release.14,38,4042 Biogenesis of exosomes is influenced by several external factors including cell type, cell confluency, serum conditions, and the presence and absence of cytokines and growth factors. In addition, biogenesis is also regulated by the sites of exosomes, protein sorting, physico-chemical aspects, and trans-acting mediators (Figure 2). For example, THP-1 cells were cultured in RPMI-1640 cell culture medium supplemented with 10% FCS secreted low level of exosomes compared to cells grown on cell culture medium supplemented with 1% FCS (Figure 3). The exogenous factor like serum starvation influences biogenesis and secretion of exosomes.

Figure 1 Biogenesis and cargoes of exosomes.

Figure 2 Effect of various factors on biogenesis of exosomes.

Figure 3 Serum deprivation causes an increase of the number of cellular exosomes in THP-1 cells. Panel (A); 10% FCS. Panel (B); 1% FCS. Panel (C) Quantification of exosomes using DLS and NTA.

Exosome release depends on expression of Rab27 or Ral. For example, exosomes released from the MVB significantly decrease in cells depleted of Rab2741 or Ral.43 The most efficient EV-producing cell types have yet to be determined44 and few reports suggest that immature dendritic cells produce limited amounts of EVs45,46 whereas mesenchymal stem cells secrete vast amounts, relevant for the production of EV therapeutics on a clinical scale.47,48 A few proteins play a critical role in the biogenesis of EVs, such as Rab27a and Rab27b.49 Over expression of Rab27a and Rab27b produce significant amounts of EVs in cancer cells. For example, overexpression of Rab27a and Rab27b in breast cancer cells,50 hepatocellular carcinoma cells,51 glioma cells,52 and pancreas cancer cells53 produces significant levels of EVs. Although all types of cells secrete and release EVs, cancer cells seem to produce higher levels than normal cells.54 Furthermore, the presence of invadopodia that are docking sites for Rab27a-positive MVBs induces secretion of EVs, and also enhances secretion of EVs in cancer cells.55 Thus, inhibition of invadopodia formation greatly reduces exosome secretion into conditioned media. This evidence demonstrates that cancer cells potentially release more EVs than non-cancer cells.

The rate of origin of exosomes from the plasma membrane of stem cells is vigorous, at rates equal to the production of exosomes,56 which is consistent with a report suggesting that stem cells bud ~50100 nm-diameter vesicles directly from the plasma membrane.57 Plasma membrane-derived exosomes contain selectively enriched protein and lipid markers in leukocytes.58 Plasma membrane exosomal budding is also observed for glioblastoma exosomes.59 Conventional transmission electron microscopy revealed that certain cell types contain deep invaginations of the plasma membrane that are indistinguishable from MVBs.6062 Certain cell types secrete exosomes containing cargo proteins, which primarily bud from the plasma membrane, and exosome composition is determined predominantly by intracellular protein trafficking pathways, rather than by the distinct mechanisms of exosome biogenesis.63 Biogenesis of exosomes is regulated by syndecan heparan sulphate proteoglycans and their cytoplasmic adaptor syntenin. Syntenin interacts directly with ALIX through LYPX (n) L motifs.64 Glycosylation is an essential factor in the biogenesis of exosomes and N-linked glycosylation directs glycoprotein sorting into EMVs.65 Collectively, these reports suggest that exosomes are made at both plasma and endosome membranes rather than endosome alone. Oligomerization is a critical factor for exosomal protein sorting and it was found to be sufficient to target plasma membrane proteins to exosomes. High-order oligomeric proteins target them to exosomes.66 Further, plasma membrane anchors support exosomal protein budding. For example, budding of CD63 and CD9 from the plasma membrane is much more efficient than endosome-targeted budding of CD63 and CD9.63 Protein clustering is another factor that induces membrane scission.67

Physico-chemical properties determine budding efficiency and are crucial factors of exosome biogenesis, a fundamental process involving the budding of vesicles that are 30200 nm in size. In particular, lipids are critical players in exosome biogenesis, especially those able to form cone and inverse cone shapes. Generally, exosome membranes contain phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylinositols (PIs), phosphatidic acid (PA), cholesterol, ceramides, sphingomyelin, glycosphingolipids, and a number of lower abundance lipids.68,69 Exosomes have a rich content of PE and PS, which increase budding efficiency and promote exosome genesis and release. PA promotes exosome biogenesis and PLD2 is involved in the budding of certain exosomal cargoes.70 Besides these factors, ceramide is an important lipid molecule regulating exosome biogenesis and facilitating membrane curvature, which is essential for vesicular budding. Inhibition of an enzyme that generates ceramide impairs exosome biogenesis.71

The next critical factor is trans-acting mediators that are involved in the biogenesis of exosomes through regulating plasma membrane homeostasis, intracellular protein trafficking pathways, MVB maturation and trafficking, IPMC biogenesis, vesicle budding, and scission.11 For example, Rab proteins regulate exosome biogenesis via endosomes and the plasma membrane by determining organelle membrane identity, recruiting mechanistic effectors, and mediating organelle dynamics.72 The functions of Rab proteins in the control and biogenesis of exosomes depends on cell type. MVB biogenesis is regulated by Rab27a, Rab27b, their effectors Slp4, Slac2b, and Munc13-4, and also Rab 35 and Rab 11.73 Loss of Rab27 function leads to a ~5075% drop in exosome production, and is also involved in assembling the plasma membrane microdomains involved in plasma membrane vesicle budding, by regulating plasma membrane PIP2 dynamics.74 Overall, Rab27 proteins control exosome biogenesis at both endosomes and plasma membranes. In addition, Rab35 also contributes to exosome biogenesis by regulating PIP2 levels of plasma membrane, and its loss leads to a reduction of exosome release by ~50%.75 Gurunathan et al76 reported that yeast produces two classes of secretory vesicles, low density and high density, and dynamin and clathrin are required for the biogenesis of these two different types of vesicle.

The Ral family is involved in the biogenesis of exosomes, and inhibition of Ral causes an accumulation of MVBs near the plasma membrane and a ~50% decrease in the vesicular secretion of exosomes and exosomal marker proteins.43 Ral GTPases function through various effectors proteins, including Arf6 and the phospholipase PLD2, which are involved in exosomal release of SDCs.37 The ESCRT complex machinery (0 through III) are involved in MVB biogenesis on a major level including membrane deformation, sealing, and repair during a wide array of processes. The major contributions of the ESCRT complex to the biogenesis of vesicles are the recognition and sequestration of ubiquitinated proteins to specific domains of the endosomal membrane via ubiquitin binding subunits of ESCRT-0. After interaction with the ESCRT-I and -II complexes, the total complex will then combine with ESCRT-III, a protein complex that is involved in promoting the budding process. Finally, following cleaving of the buds to form ILVs, the ESCRT-III complex separates from the MVB membrane using energy supplied by the sorting protein Vps4.77 In addition, other proteins such as Alix, which is associated with several ESCRT (TSG101 and CHMP4) proteins, are involved in endosomal membrane budding and abscission, as well as exosomal cargo selection via interaction with syndecan.39 Another important factor, autophagy, is critically involved in exosome secretion. Autophagy related (Atg) proteins coordinate initiation, nucleation, and elongation during autophagosome biogenesis in the presence of ESCRT-III components including CHMP2A and VPS4. For instance, the absence of Atg5 in cancer cells causes a reduction in exosome production.78 Conversely, CRISPR/Cas9-mediated knockout of Atg5 in neuronal cells increases the release of exosomes and exosome-associated prions from neuronal cells.79

Exosomes play a critical role in the physiologic regulation of mammary gland development and are important mediators of breast tumorigenesis.80 Biogenesis of exosomes occurs in all cell types; however, production depends on cell type. For example, breast cancer cells (BCC) produce increased numbers of exosomes compared to normal mammary epithelial cells. Studies revealed that patients with BC have increased numbers of MVs in their blood.81 Kavanagh et al reported that several fold changes were observed from exosomes isolated from triple negative breast cancer (TNBC) chemoresistant therapeutic induced senescent (TIS) cells compared with control EVs.82 TIS cells release significantly more EVs compared with control cells, containing chemotherapy and key proteins involved in cell proliferation, ATP depletion, and apoptosis, and exhibit the senescence-associated secretory phenotype (SASP). Cannabidiol (CBD), inhibits exosome and microvesicle (EMV) release in three different types of cancer cells including prostate cancer (PC3), hepatocellular carcinoma (HEPG2), and breast adenocarcinoma (MDA-MB-231). All three different cell lines show variability in the release of exosomes in a dose-dependent manner. These variabilities are all due to mitochondrial function, including modulation of STAT3 and prohibitin expression. This study suggests that the anticancer agent CBD plays critical role in EMV biogenesis.83 Sulfisoxazole (SFX) inhibits sEV secretion from breast cancer cells through interference with endothelin receptor A (ETA) through the reduced expression of proteins involved in the biogenesis and secretion of sEV, and triggers co-localization of multivesicular endosomes with lysosomes for degradation.84 Secreted EVs from human colorectal cancer cells contain 957 vesicular proteins. The direct protein interactions between cellular proteins play a critical role in protein sorting during EV formation. SRC signaling plays a major role in EV biogenesis, and inhibition of SRC kinase decreases the intracellular biogenesis and cell surface release of EVs.85 Proteomic analysis revealed that the exosomes released from imatinib-sensitive GIST882 cell line exhibit 764 proteins. The authors found that significant amount of proteins belong to protein release function and involved in the classical pathway and overlap to a high degree with proteins of exosomal origin.86 Exosomes secreted by antigen-presenting cells contain high levels of MHC class II proteins and costimulatory proteins, whereas exosomes released from other cell types lack these proteins.1,87

The biogenesis of exosomes depends on a percentage of confluency of approximately 6090%, which influences the yield and functions of EVs.44 Gal et al88 observed a 10-fold decreased level of cholesterol metabolism in confluent cell cultures compared to cells in the preconfluent state. The high level of cholesterol content in confluent cells leads to a decreased level of EVs in prostate cancer.68 The major reason behind for the reduced level of vesicle production is contact inhibition, which triggers confluent cells to enter quiescence and/or alters their characteristics compared to actively dividing cells.89,90 Exogenous stimulation could influence the condition of the cells including the phenotype and efficacy of secretion. Previously, several studies demonstrated that various external factors increase biogenesis of EVs such as Ca2+ ionophores,91 hypoxia,9294 and detachment of cells,95 whereas lipopolysaccharide reduces biogenesis and release of EVs.96 Furthermore, serum, which supports adherence of the cells, plays a critical role in the biogenesis of EVs.97 For example, FCS has noticeable effects on cultured cells; however, the effects depend on cell type and differentiation status.97,98 To avoid the immense amounts of vesicles present in FCS, the use of conditioned media has been suggested. Culture viability and health status of cells are important aspects for producing an adequate amount of vesicles with proper cargo molecules such as protein and RNA.99,100 Exogenous stress, such as starvation, can induce phenotypic alterations and changes in proliferation. These changes cause alterations in the cells metabolism and eventually lead to low yields.101,102

Cellular stresses, such as hypoxia, inflammation, and hyperglycemia, influence the RNA and protein content in exosomes. To examine these factors, the effects of cellular stresses on endothelial cells were studied.99 Endothelial cells were exposed to different types of cellular stress such as hypoxia, tumor necrosis factor- (TNF-)-induced activation, and high glucose and mannose concentrations. The mRNA and protein content of exosomes produced by these cells were compared using microarray analysis and a quantitative proteomics approach. The results indicated that endothelial cell-derived exosomes contain 1354 proteins and 1992 mRNAs. Several proteins and mRNAs showed altered levels after exposure of their producing cells to cellular stress. Interestingly, cells exposed to high sugar concentrations had altered exosome protein composition only to a minor extent, and exosome RNA composition was not affected. Low-intensity ultrasound-induced (LIUS) anti-inflammatory effects have been achieved by upregulation of extracellular vesicle/exosome biogenesis. These exosomes carry anti-inflammatory cytokines and anti-inflammatory microRNAs, which inhibit inflammation of target cells via multiple shared and specific pathways. A study suggested that exosome-mediated anti-inflammatory effects of LIUS are feasible and that these techniques are potential novel therapeutics for cancers, inflammatory disorders, tissue regeneration, and tissue repair.103 Another factor, called manumycin-A (MA), a natural microbial metabolite, was analyzed in exosome biogenesis and secretion in castration-resistant prostate cancer (CRPC) C4-2B, cells. The effect of MA on cell growth was observed, and the results revealed that there was no effect on cell growth. However, MA attenuated the ESCRT-0 proteins Hrs, ALIX, and Rab27a, and exosome biogenesis and secretion by CRPC cells. The inhibitory effect of MA on exosome biogenesis and secretion was primarily mediated via targeted inhibition of Ras/Raf/ERK1/2 signaling. These findings suggest that MA is a potential drug candidate for the suppression of exosome biogenesis and secretion by CRPC cells.104

Methods of isolation of exosomes play critical roles in functions and delivery. Although several methods such as ultracentrifugation, density gradient centrifugation, chromatography, filtration, polymer-based precipitation, and immunoaffinity have been adopted to isolate pure exosomes without contamination, there is still a lack of consistency and agreement.105 Isolation of exosomes along with non-exosomal materials and damaged exosomal membranes creates artifacts and alters the protein and RNA profiles. Since exosomes are obtained from a variety of sources, the composition of proteins/lipids influences the sedimentation properties and isolation. Thus, precise and consistent techniques are warranted for the isolation, purification, and application of exosomes.

Although several functions of exosomes have been explored, the precise function of exosomes remains a mystery. Historically, exosomes have been known to function as cellular garbage bags, recyclers of cell surface proteins, cellular signalers, intercellular signaling and cell-cell communications, immune responses, cellular homeostasis, autophagy, and infectious diseases.106 (Figure 4) ECVs are secreted cell-derived membrane particles involved in intercellular signaling and cell-cell communications, and contain immense bioactive information. Most cell types produce exosomes and release these into the extracellular environment, circulating through different bodily fluids such as urine, blood, and saliva and transferring their cargo to recipient cells. These vesicles play a significant role in various pathological conditions, such as different types of cancer, neurodegenerative diseases, infectious diseases, pregnancy complications, obesity, and autoimmune diseases, as reviewed elsewhere.107 Exosomes play a significant role in intercellular communication between cells by interacting with target cells via endocytosis.108 More specifically, exosomes are involved in cancer development, survival and metastasis of tumors, drug resistance, remodeling of the extracellular matrix, angiogenesis, thrombosis, and proliferation of tumor cells.94,109111 Exosomes contribute significantly to tumor vascularization and hypoxia-mediated inter-tumor communication during cancer progression, and premetastatic niches, which are significant players in cancer.16,94,109,112 Exosomes derived from hepatic epithelial cells increase the expression of enhancer zeste homolog 2 (EZH2) and cyclin-D1, and subsequently promotes G1/S transition.113

Figure 4 Multifunctional aspects biological functions of exosomes.

Conventionally, cells communicate with adjacent cells through direct cell-cell contact through gap junctions and cell surface protein/protein interactions, whereas cells communicating with distant cells do so through secreted soluble factors, such as hormones and cytokines, to facilitate signal propagation.114 Cells also communicate through electrical and chemical signals.115 Several studies have suggested that exosomes play vital roles in intercellular communication by serving as vehicles for transferring various cellular constituents, such as proteins, lipids, and nucleic acids, between cells.6,116118 Exosomes function as exosomal shuttle RNAs in which some exosomal RNAs from donor cells functions in recipient cells,6 a form of genetic exchange. Recently, researchers found that cells communicating with other cells through exosomes carrying cell-specific cargoes of proteins, lipids, and nucleic acids may employ novel intercellular communication mechanisms.30 Exosomes exert influences through various mechanistic approaches, such as direct stimulation of target cells via surface-bound ligands; transfer of activated receptors to recipient cells; and epigenetic reprogramming of recipient cells.119,120 Exosomes play critical roles in immunoregulation, including antigen presentation, immune activation, immune suppression, and immune tolerance via exosome-mediated intercellular communication. Mesenchymal stem cell (MSC)-derived exosomes play significant roles in wound healing processes.121 Exosomes from platelet-rich plasma (PRP) inhibit the release of TNF-. PRP-Exos significantly decreases the apoptotic rate of osteoarthritis (OA) chondrocytes compared with activated PRP (PRP-As).122 Extracellular vesicle (ECV)-modified polyethylenimine (PEI) complexes enhance short interfering RNA (siRNA) delivery by forming non-covalent complexes with small RNA molecules, including siRNAs and anti-miRs, in both conditions, in vitro and in vivo.123 Non-GSC glioma cells were treated with GSC-released exosomes. The results showed that GSC-released exosomes increase proliferation, neurosphere formation, invasive capacities, and tumorigenicity of non-GSC glioma cells through the Notch1 signaling pathway and stemness-related protein expressions.124

Exosomal miR-1910-3p promotes proliferation and migration of breast cancer cells in vitro and in vivo through downregulation of myotubularin-related protein 3 and activation of the nuclear factor-B (NF-B) and wnt/-catenin signaling pathway, and promotes breast cancer progression.125 Human hepatic progenitor cell (CdH)-derived exosomes (EXOhCdHs) play a crucial role in maintaining cell viability and inhibit oxidative stress-induced cell death. Experimental evidence suggests that inhibition of exosome secretion treatment with GW4869 results in the acceleration of reactive oxygen species (ROS) production, thereby causing a decrease in cell viability.126 Tumor-derived EXs (TDEs) are vehicles that enable communication between cells by transferring bioactive molecules, also delivering oncogenic molecules and containing different molecular cargoes compared to EXs delivered from normal cells. They can therefore be used as non-invasive biomarkers for the early diagnosis and prognosis of most cancers, including breast and ovarian cancers.127 Exosomes released by ER-stressed HepG2 cells significantly enhance the expression levels of several cytokines, including IL-6, monocyte chemotactic protein-1, IL-10, and tumor necrosis factor- in macrophages. ER stress-associated exosomes mediate macrophage cytokine secretion in the liver cancer microenvironment, and also indicate the potential of treating liver cancer via an ER stress-exosomal-STAT3 pathway.128 Mesenchymal stem cell-derived exosomal miR-223 protects neuronal cells from apoptosis, enhances cell migration and increases miR-223 by targeting PTEN, thus activating the PI3K/Akt pathway. In addition, exosomes isolated from the serum of AD patients promote cell apoptosis through the PTEN-PI3K/Akt pathway and these studies indicate a potential therapeutic approach for AD.129 A mouse model of diabetes demonstrated that mesenchymal stromal cell-derived exosomes ameliorate peripheral neuropathy through increased nerve conduction velocity. In addition, MSC-derived exosomes substantially suppress proinflammatory cytokines.130

Exosomes derived from activated astrocytes promote microglial M2 phenotype transformation following traumatic brain injury (TBI). miR-873a-5p significantly inhibits LPS-induced microglial M1 phenotype transformation.131 Several studies reported that exosomes are involved in cancer progression and metastasis; however, this depends on the type of cells the exosomes were derived from. For example, human umbilical vein endothelial cells (HUVEC) were treated with exosomes derived from HeLa cells (ExoHeLa), and the expression of tight junctions (TJ) proteins, such as zonula occludens-1 (ZO-1) and Claudin-5, was significantly reduced compared with exosomes from human cervical epithelial cells. Thus, permeability of the endothelial monolayer was increased after the treatment with ExoHeLa. Mice studies have shown that injection of ExoHeLa into mice increased vascular permeability and tumor metastasis. The results from this study demonstrated that HeLa cell-derived exosomes promote metastasis by triggering ER stress in endothelial cells and break down endothelial integrity. Such effects of exosomes are microRNA-independent.132 Exosomes mediate the gene expression of target cells and regulate pathological and physiological processes including promoting angiogenesis, inhibiting ventricular remodeling and improving cardiac function, as well as inhibiting local inflammation and regulating the immune response. Accumulating evidence shows that exosomes possess therapeutic potential through their anti-apoptotic and anti-fibrotic roles.

The functions of exosomes in immune responses are well established and do not cause any severe immune responses. A mouse study demonstrated that administration of a low dose of mouse or human cell-derived exosomes for extended periods of time caused no severe immune reactions.133 The function of exosomes in immune regulation is regulated by the transfer and presentation of antigenic peptides. Exosomes contain antigen-presenting cells (APCs) carrying peptide MHC-II and costimulatory signals and directly present the peptide antigen to specific T cells to induce their activation.134 For example, intradermal injection of APC-derived exosomes with MHC-II loaded with tumor peptide delayed tumor progression and growth.135 Exosome-derived immunogenic peptides activate immature mouse dendritic cells and indirectly activate APCs, and induce specific CD4+ T cell proliferation.136 Exosomes containing IFNa and IFNg, tumor necrosis factor a (TNFa), and IL from macrophages promoted dendritic cell maturation, CD4+ and CD8+ T cell activation, and the regulation of macrophage IL expression.137 The cargo of exosomes, such as DNA and miRNA, regulate the innate and adaptive immune responses. Exosomes are able to regulate the immune response by controlling gene expression and signaling pathways in recipient cells through transfer of miRNAs, and eventually control dendritic cell maturation.138 Exosomes containing miR-212-3p derived from tumors down-regulate the MHC-II transcription factor RFXAP (regulatory factor X associated protein) in dendritic cells, possibly promoting immune evasion by cancer cells.139 Exosomes containing miR-222-3p down regulate expression of SOCS3 (suppressor of cytokine signaling 3) in monocytes, which is involved in STAT3-mediated M2 polarization of macrophages.140 In mice, exosomes stimulate adaptive immune responses, including the activation of dendritic cells, with the uptake of breast cancer cell-derived exosomal genomic DNA and activation of cGAS-STING signaling and antitumor responses.141 The priming of dendritic cells is associated with the uptake of exosomal genomic and mitochondrial DNA (mtDNA) from T cells, inducing type I IFN production by cGAS-STING signaling.142 Inhibition of EGFR leads to increased levels of DNA in the exosomes and induces cGAS-STING signaling in dendritic cells, contributing to the overall suppression of tumor growth.143 Conversely, uptake of tumor-derived exosomal DNA by circulating neutrophils was shown to enhance the production of tissue factor and IL-8, which play a role in promoting tumor inflammation and paraneoplastic events.144 Melanoma-derived exosomes containing PD-L1 (programmed cell death ligand 1) suppress CD8+ T cell antitumor function and cancer cell-derived exosomes block dendritic cell maturation and migration in a PD-L1-dependent manner. Engineered cancer cell-derived exosomes promote dendritic cell maturation, resulting in increased proliferation of T cells and antitumor activity.145147

Inflammation is an important process for maintaining homeostasis in cellular systems. Systemic inflammation is an essential component in the pathogenesis of several diseases.148,149 Exosomes seem to play a crucial role in inflammation processes through cargo molecules, such as miRNA and proteins, which act on nearby as well as distant target tissues. Exosomes play a vital role in intercellular communication between cells via endocytosis and are associated with modulation of inflammation, coagulation, angiogenesis, and apoptosis.20,150153 Exosomes derived from dendritic cells, B lymphocytes, and tumor cells release exosomes that can regulate immunological memory through the surface expression of antigen-presenting MHC I and MHC II molecules, and subsequently elicit T cell activation and maturation.134,137,154156 Exosomes play a crucial role in carrying and presenting functional MHC-peptide complexes to modulate antigen-specific CD8+ and CD4+ responses.157,158 Exosomes containing miR-Let-7d influence the growth of T helper 1 (Th1) cells and inhibit IFN- secretion.159 Exosomes derived from choroid plexus epithelial cells containing miR-146a and miR-155 upregulate the expression of inflammatory cytokines in astrocytes and microglia.160 Exosomes containing miR-181c suppress the expression of Toll-like receptor 4 (TLR-4) and subsequently lower TNF- and IL-1 levels in burn-induced inflammation.161 Exosomal miR-155 from bone marrow cells (BMCs) increases the level of TNF- and subsequently enhances innate immune responses in chronic inflammation.162 Exosomes containing miR-150-5p and miR-142-3p derived from dendritic cells (DCs) increase expression of interleukin 10 (IL-10) and a decrease in IL-6 expression.163 Exosomal miR-138 can protect against inflammation by decreasing the expression level of NF-B, a transcription factor that regulates inflammatory cytokines such as TNF- and IL-18.164 HIF-1-inducing exosomal microRNA-23a expression from tubular epithelial cells mediates the cross talk between tubular epithelial cells and macrophages, promoting macrophage activation and triggering tubulointerstitial inflammation.165 A rat model study demonstrated that bone marrow mesenchymal stem cell (BMSC)-derived exosomes reduced inflammatory responses by modulating microglial polarization and maintaining the balance between M2-related and M1-related cytokines.165 Melatonin-stimulated mesenchymal stem cell (MSC)-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway, and significantly suppressed the pro-inflammatory factors IL-1 and TNF- and reduced the relative gene expression of IL-1, TNF-, and iNOS. Increasing levels of anti-inflammatory factor IL-10 are associated with increasing relative expression of Arg-1.166

Immunomodulators are essential factors for the prevention and treatment of disorders occurring due to an over high-spirited immune response, such as the SARS-CoV-2-triggered cytokine storm leading to lung pathology and mortality seen during the ongoing viral pandemic.167 MSC-secreted extracellular vesicles exhibit immunosuppressive capacity, which facilitates the regulation of the migration, proliferation, activation, and polarization of various immune cells, promoting a tolerogenic immune response while inhibiting inflammatory responses.168 Collagen scaffold umbilical cord-derived mesenchymal stem cell (UC-MSC)-derived exosomes induce collagen remodeling, endometrium regeneration, increasing the expression of the estrogen receptor /progesterone receptor, and restoring fertility. Furthermore, exosomes modulate CD163+ M2 macrophage polarization, reduce inflammation, increase anti-inflammatory responses, facilitate endometrium regeneration, and restore fertility through the immunomodulatory functions of miRNAs.169 Exosomes released into the airways during influenza virus infection trigger pulmonary inflammation and carry viral antigens and it facilitate the induction of a cellular immune response.170 Shenoy et al171 reported that exosomes derived from chronic inflammatory microenvironments contribute to the immune suppression of T cells. These exosomes arrest the activation of T cells stimulated via the T cell checkpoint (TCR). Exosomes secreted by normal retinal pigment epithelial cells (RPE) by rotenone-stimulated ARPE-19 cells induce apoptosis, oxidative injury, and inflammation in ARPE-19 cells. Exosomes secreted under oxidative stress induce retinal function damage in rats and upregulate expression of Apaf1. Overexpression of Apaf1 in exosomes secreted under oxidative stress (OS) can cause the inhibition of cell proliferation, increase in apoptosis, and elicitation of inflammatory responses in ARPE-19 cells. Exosomes derived from ARPE-19 cells under OS regulate Apaf1 expression to increase apoptosis and to induce oxidative injury and inflammatory response through a caspase-9 apoptotic pathway.172 Collectively, these findings highlight the critical role of exosomes in inflammation and suggest the possibility of utilizing exosomes as an inducer to attenuate inflammation and restore impaired immune responses in various diseases including cancer.

The endomembrane system of eukaryotic cells is a complex series of interconnected membranous organelles that play vital roles in protecting cells from adverse conditions, such as stress, and maintaining cell homeostasis during health and disease.173 To preserve cellular homeostasis, higher eukaryotic cells are equipped with various potent self-defense mechanisms, such as cellular senescence, which blocks the abnormal proliferation of cells at risk of neoplastic transformation and is considered to be an important tumor-suppressive mechanism.174,175 Exosomes contribute to reduce intracellular stress and preservation of cellular homeostasis through clearance of damaged or toxic material, including proteins, lipids, and even nucleic acids. Therefore, exosomes serve as quality controller in cells.176 The vesicular transport system plays pivotal roles in the maintenance of cell homeostasis in eukaryote cells, which involves the cytoplasmic trafficking of biomolecules inside and outside of cells. Several types of membrane-bound organelles, such as the Golgi apparatus, endoplasmic reticulum (ER), endosomes and lysosomes, in association with cytoskeleton elements, are involved in the intracellular vesicular system. Molecules are transported through exocytosis and endocytosis to maintain homeostasis through the intracellular vesicular system and regulate cells responses to the internal and external environment. To maintain homeostasis and protect cells from various stress conditions, autophagy is an intracellular vesicular-related process that plays an important role through the endocytosis/lysosomal/exocytosis pathways through degradation and expulsion of damaged molecules out of the cytoplasm.177179 Autophagy, as an intracellular waste elimination system, is a synchronized process that actively participates in cellular homeostasis through clearance and recycling of damaged proteins and organelles from the cytoplasm to autophagosomes, and then to lysosomes.38,180182 Cells maintain homeostasis by autophagosomes, which are vesicles derived from autophagic and endosomal compartments. These processes are involved in adaption to nutrient deprivation, cell death, growth, and tumor progression or suppression. Autophagy flux contributes to maintaining homeostasis in the tumor microenvironment of endothelial cells. To support this concept, a study provided evidence suggesting that depletion of Atg5 in ECs could intensify the abnormal function of tumor vessels.183 Exosome secretion plays a crucial role in maintaining cellular homeostasis in exosome-secreting cells. As a consequence of blocking exosome secretion, nuclear DNA accumulates in the cytoplasm, thereby causing the activation of cytoplasmic DNA sensing machinery. Blocking exosome secretion aggravates the innate immune response, leading to ROS-dependent DNA damage responses and thus inducing senescence-like cell-cycle arrest or apoptosis in normal human cells. Thus, cells remove harmful cytoplasmic DNA, protecting them from adverse effects.182 Salomon and Rice reported that the involvement of exosomes in placental homeostasis and pregnancy disorders. EVs of placental origin are found in a variety of body fluids including urine and blood. Moreover, the number of exosomes throughout gestation is higher in complications of pregnancy, such as preeclampsia and gestational diabetes mellitus, compared to normal pregnancies.184

The endolysosomal system is critically involved in maintaining homeostasis through the highly regulated processes of internalization, sorting, recycling, degradation, and secretion. For example, endocytosis allows the internalization of various receptor proteins into cells, and vesicles formed from the plasma membrane fuse and deliver their membrane and protein content to early endosomes. Similarly, significant amounts of internalized content are recycled back to the plasma membrane via recycling endosomes,76 while the remaining material is sequestered in ILVs in late endosomes, also known as multivesicular bodies.185,186 Tetraspanin proteins, such as CD63 and CD81, are regulators of ILV formation. Once ILVs are formed, MVBs can degrade their cargo by fusing with lysosomes or, alternatively, MVBs can secrete their ILVs by fusing with the plasma membrane and release their content into extracellular milieu.187190 Exosomes play an important role in regulating intracellular RNA homeostasis by promoting the release of misfolded or degraded RNA products, and toxic RNA products. Y RNAs are involved in the degradation of structured and misfolded RNAs. Further studies have demonstrated that proteins involved in RNA processing are abundant in exosomes, and the half-lives of secreted RNAs are almost twice as short as those of intracellular mRNAs. These studies suggest that cells maintain intracellular RNA homeostasis through the release of distinct RNA species in extracellular vesicles.191193 Exosomes reduce cholesterol accumulation in Niemann-Pick type C disease, a lysosomal storage disease in which cells accumulate unesterified cholesterol and sphingolipids within the endosomal and lysosomal compartment.194

Autophagy is the intracellular vesicular-related process that regulates the cell environment against pathological and stress conditions. In order to maintain homeostasis and protect the cells against stress conditions, internal vesicles or secreted vesicles serve as a canal to degrade and expel damaged molecules out of the cytoplasm.38,181,182 Autophagy protects the cell from various stress conditions and maintains cellular homeostasis, regulating cell survival and differentiation through clearance and recycling of damaged proteins and organelles from the cytoplasm to autophagosomes, and then to lysosomes.180 Several studies have demonstrated that proteins are involved in controlling tumor cell function and fate, and mediate crosstalk between exosome biogenesis and autophagy. Coordination between exosome-autophagy networks serves as a tool to conserve cellular homeostasis via the lysosomal degradative pathway and/or secretion of cargo into the extracellular milieu.176,195 Autophagy is a multi-step process that occurs by initiation, membrane nucleation, maturation and finally the fusion of autophagosomes with lysosomes. The autophagy process is not only linked with endocytosis but is also linked with the biogenesis of exosomes. For example, subsets of the autophagy machinery involved in the biogenesis of exosomes and the autophagic process itself appear dispensable.78,196 Crosstalk between exosomal and autophagic pathways has been reported in a growing number of diseases. Proteomic studies were performed to analyze the involvement of key proteins in the interconnection between exosome and autophagy pathways. They found that almost all proteins were identified; however, their involvement differed between them. Among 100 proteins, four proteins were highly ranked including HSPA8 (3/100), HSP90AA1 (8/100), VCP (24/100), and Rab7A (81/100). These data suggest an interconnection between the exosome and autophagy.197,198 Endosomal autophagy plays a significant role in the interconnection between exosomes and autophagy. Stress is a major factor for autophagy. In particular, the starvation of cells is a key inducer of autophagy, and induces enlargement of MVB structures and a co-localization of Rab11 and LC3 in these structures, an indication that autophagy-related processes are associated with the MVB.199 The sorting of autophagy-related cargo into MVBs is dependent on Hsc70 (HSPA8), VPS4, and TSG101, and independent on LAMP-2A, thereby excluding a role for, the lysosome.200 Several proteins are involved in the regulation and biogenesis of secretory autophagy compartments such as GRASPs, LC3, Rab8a, ESCRTs, and SNAREs, along with several Atg proteins.181,201,202 Autophagosomes could fuse with MVBs to form amphisomes and release vesicles to the external environment.203

Autophagy and exosome biogenesis and function are interconnected by microRNA. Over-expression of miR-221/222 inhibits the level of PTEN and activates Akt signaling, and subsequently reduces the expression of hallmarks that positively relate to autophagy including LC3, ATG5 and Beclin1, and increases the expression of SQSTM1/p62.204 MiR-221/222 from human aortic smooth muscle cell (HAoSMC)-derived exosomes inhibit autophagy in HUVECs by modulating the PTEN/Akt signaling pathway. miRNA-223 attenuates hypoxia-induced apoptosis and excessive autophagy in neonatal rat cardiomyocytes and H9C2 cells via the Akt/mTOR pathway, by targeting poly(ADP-ribose) polymerase 1 (PARP-1) through increased autophagy via the AMPK/mTOR and Akt/mTOR pathways205 ATG5 mediates the dissociation of vacuolar proton pumps (V1Vo-ATPase) from MVBs, which prevents acidification of the MVB lumen and allows MVB-PM fusion and exosome release. Accordingly, knockout of ATG5 or ATG16L1 significantly reduces exosome release and attenuates the exosomal enrichment of lipidated LC3B. These findings demonstrate that autophagic mechanisms possibly regulate the fate of MVBs and subsequent exosome biogenesis.78 Bone marrow MSC (BMMSC)-derived exosomes contain a high level of miR-29c, which regulates autophagy under hypoxia/reoxygenation (H/R) conditions.206 Human umbilical cord MSC-derived exosomes (HucMDEs) promote hepatic glycolysis, glycogen storage, and lipolysis, and reduce gluconeogenesis. Additionally, autophagy potentially contributes to the effects of HucMDE treatment and increases formation of autophagosomes and the autophagy marker proteins BECN1, MAP, and 1LC3B. These findings suggest that HucMDEs improve hepatic glucose and lipid metabolism in T2DM rats by activating autophagy via the AMPK pathway.207 Liver fibrosis is a serious disorder caused by prolonged parenchymal cell death, leading to the activation of fibrogenic cells, extracellular matrix accumulation, and eventually liver fibrosis. Exosomes derived from adipose-derived mesenchymal stem cells (ADSCs) have been used to deliver circular RNAs mmu_circ_0000623 to treat liver fibrosis. The findings from this study suggest that Exos from ADSCs containing mmu_circ_0000623 significantly suppress CCl4-induced liver fibrosis by promoting autophagy activation. Autophagy inhibitor treatment significantly reverses the treatment effects of Exos.208 Inhibition of autophagy by PDGF and its downstream molecule SHP2 (Src homology 2-containing protein tyrosine phosphatase 2) increased hepatic stellate cell (HSC)-derived EV release. Disruption of mTOR signaling abolishes PDGF-dependent EV release. Activation of mTOR signaling induces the release of MVB-derived exosomes by inhibiting autophagy, as well as microvesicles, through activation of ROCK1 signaling. Furthermore, deletion of SHP2 attenuates CCl4 or BDL-induced liver fibrosis.209 The therapeutic effects of exosomes containing high concentrations of mmu_circ_0000250 were analyzed in diabetic mice. The findings indicated that a high concentration of mmu_circ_0000250 had a better therapeutic effect on wound healing when compared with wild-type exosomes from ADSCs. The results also showed that exosome treatment with mmu_circ_0000250 increased angiopoiesis in wounded skin and suppressed apoptosis by inducing miR-128-3p/SIRT1-mediated autophagy.210 A study showed that mice treated with differentiated cardiomyocyte (iCM) exosomes exhibited significant cardiac improvement post-myocardial infarction, with significantly reduced apoptosis and fibrosis. Apoptosis was associated with reduced levels of hypoxia and inhibition of exosome biogenesis. iCM-exosome-treated groups showed upregulation of autophagosome production and autophagy flux. Hence, these findings indicate that iCM-Ex can improve post-myocardial infarction cardiac function by regulating autophagy in hypoxic cardiomyocytes.211 Exosomes of hepatocytes play a crucial role in inhibiting hepatocyte apoptosis and promoting hepatocyte regeneration. Mesenchymal stem cell-derived hepatocyte-like cell exosomes (MSC-Heps-Exo) were injected into a mouse hepatic Ischemia/reperfusion (I/R) I/R model through the tail. The results demonstrated that MSC-Heps-Exo effectively relieve hepatic I/R damage, reduce hepatocyte apoptosis, and decrease liver enzyme levels. A possible mechanism of reduced hepatic ischemia/reperfusion injury is the enhancement of autophagy.212

Exosomes play a critical role in viral infections, particularly of retroviruses and retroviruses, and use preexisting pathways for intracellular protein trafficking and formation of infectious particles. Exosomes and viruses share several features including biogenesis, uptake by cells, and the intracellular transfer of RNAs, mRNAs, and cellular proteins. Some features are different, including self-replication after infection of new cells, regulation of viral expression, and complex viral entry mechanisms.213,214 Exosomes secreted from virus-infected cells carry mostly cargo molecules such as viral proteins, genomic RNA, mRNA, miRNA, and genetic regulatory elements.215218 These cargo molecules are involved in the alteration of recipient cell behavior, regulating cellular responses, and enabling infection by various types of viruses such as human T-cell lymphotropic virus (HTLV), hepatitis C virus (HCV), dengue virus, and human immunodeficiency virus (HIV).215 Exosomes communicate with host cells through contact between exosomes and their recipient cells, via different kinds of mechanisms. Initially, the transmembrane proteins of exosomes build a network directly with the signaling receptors of target cells and then join with the plasma membrane of recipient cells to transport their content to the cytosol. Finally, the exosomes are incorporated into the recipient cells.219221 A report suggested that disruption of exosomal lipid rafts leads to the inhibition of internalization of exosomes.95 Exosomes derived from HIV-infected patients contain the trans-activating response element, which is responsible for HIV-1 replication in recipient cells through downregulation of apoptosis.222 While exosomes serving as carrier molecules, exosomes contain miRNAs that induce viral replication and immune responses either by direct targeting of viral transcripts or through indirect modulation of virus-related host pathways. In addition, exosomes have been found to act as nanoscale carriers involved in HIV pathogenesis. For example, exosomes enhance HIV-1 entry into human monocytic and T cell lines through the exosomal tetraspanin proteins CD9 and CD81.223 Influenza virus infection causes accumulation of various types of microRNAs in bronchoalveolar lavage fluid, which are responsible for the potentiation of the innate immune response in mouse type II pneumocytes. Serum of influenza virus-infected mice show significant levels of miR-483-3p, which increases the expression of proinflammatory cytokine genes and inflammatory pathogenesis of H5N1 influenza virus infection in vascular endothelial cells.224 Exosomes are involved in the transmission of inflammatory, apoptotic, and regenerative signals through RNAs. Chen et al investigated the potential functions of exosomal RNAs by RNA sequencing analysis in exosomes derived from clinical specimens of healthy control (HC) individuals and patients with chronic hepatitis B (CHB) and acute-on-chronic liver failure caused by HBV (HBV-ACLF). The results revealed that the samples contained unique and distinct types of RNAs in exosomes.225 Zika virus (ZIKV) infection causes severe neurological malfunctions including microcephaly in neonates and other complications associated with Guillain-Barr syndrome in adults. Interestingly, ZIKV uses exosomes as mediators of viral transmission between neurons and increases production of exosomes from neuronal cells. Exosomes derived from ZIKV-infected cells contained both ZIKV viral RNA and protein(s) which are highly infectious to nave cells. ZIKV uses neutral Sphingomyelinase (nSMase)-2/SMPD3 to regulate production and release of exosomes.226

During infections, viruses replicate in host cells through vesicular trafficking through a sequence of complexes known as ESCRT, and assimilate viral constituents into exosomes. Exosomes encapsulate viral antigens to maximize infectivity by hiding viral genomes, entrapping the immune system, and maximizing viral infection in uncontaminated cells. Exosomes can be used as a source of viral antigens that can be targeted for therapeutic use. A Variety of infectious diseases caused by viruses such as HCV, ZIKV, West Nile virus (WNV), and DENV enter into the host cells using clathrin-mediated or receptor-mediated endocytosis. For example, HCV infects host cells by specific targeting of cells through cellular contact, and hepatocyte-derived exosomes that contain HCV RNA can stimulate innate immune cells.217,227230 Exosomes show structural and molecular similarity to HIV-1 and HIV-2, which are enclosed by a lipid bilayer, and in the vital features of size and density, RNA species, and macro biomolecules including carbohydrates, lipids, and proteins. HIV-infected cells release enriched viral RNAs containing exosomes derived from HIV-infected cells and are enhanced with viral RNAs and Nef protein.6,38,231236 Izquierdo-Useros et al reported that both exosomes and HIV-1 express sialyllactose-containing gangliosides and interact with each other via sialic-acid-binding immunoglobulin-like lectins (Siglecs)-1. Siglecs-1 stimulates mature dendritic cell (mDC) capture and storage of both exosomes and HIV-1 in mDCs.237 Exosomes released from HIV-infected T cells contain transactivation response (TAR) element RNA, which stimulate proliferation, migration, and invasion of oral/oropharyngeal and lung cancer cells.238 Nuclear VP40 from Ebola virus VP40 upregulates cyclin D1 levels, resulting in dysregulated cell cycle and EV biogenesis. Synthesized extracellular vesicles contain cytokines and EBOV proteins from infected cells, which are responsible for the destruction of immune cells during EBOV pathogenesis.239 HIV enters into the host cells through human T-cell immunoglobin mucin (TIM) proteins. TIMs are a group of proteins (TIM-1, TIM-3, and TIM-4) that promote phagocytosis of apoptotic cells.240 TIM-4 is involved in HIV-1 exosome-dependent cellular entry mechanisms. Substantiating this hypothesis, neural stem cell (NSC)-derived exosomes containing TIM-4 protein increase HIV-1 exosome-dependent cellular entry into host cells, and antibody against TIM4 inhibits exosome-mediated entry of HIV in various types of cell.241

Exosomes show immense promise in biomedical applications due to their potential in drug delivery, the carriage of biomolecular markers of many diseases, and cellular protection. In addition, they can be used in non-invasive diagnostics or minimum invasive diagnostics.150 Detection of biomarkers is vital for early diagnosis of cancer and also critical for treatment. Several studies have documented the importance of exosomes in a variety of diseases, although further examination of the biology and functions of exosomes is warranted due to the continuing emergence of new diseases in the present world. The complex cargo of exosomes facilitates the exploration of a variety of diagnostic windows into disease detection, monitoring, and treatment. Exosomes are found in all biological fluids and are secreted by all cells, rendering them attractive for use through minimally invasive liquid biopsies, and they have the potential for use in longitudinal sampling to follow disease progression.242 Exosomes are produced and secreted by almost all body fluids, including blood, urine, saliva, breast milk, cerebrospinal fluid, semen, amniotic fluid, and ascites. These exosomes contain micro RNAs, proteins, and lipids serving as diagnostic markers.120 Exosomes are used in diagnostic applications in various kinds of diseases, such as cardiovascular diseases (CVDs),243 diseases of the central nervous system (CNS),244 cancer,245 and other prominent diseases including in the liver,246 kidney,247 and lung.248 Exosomes are potentially used to detect cancer-associated mutations in serum and also for the transfer of genomic DNA from donor cells to recipient cells.249 Exosomes carrying specific miRNAs or groups of miRNAs can be used as diagnostic markers to detect cancer. For example, exosomes containing oncogenic Kras, which have tumor-suppressor miRNAs-100, seem to have high diagnostic value, which could facilitate the differentiation of the expression pattern between cancer cells and normal cells.250,251 Similarly, miR-21 is considered to be diagnostic marker for various types of cancer including glioblastomas and pancreatic, colorectal, colon, liver, breast, ovarian, and esophageal cancers.252 Tumor suppressor miRNAs, such as miR-146a and miR-34a, function as diagnostic tools to detect liver, breast, colon, pancreatic, and hematologic malignancies.251 Exosomes containing GPC1 (glypican 1) are used as diagnostic markers to detect pancreatic, breast, and colon cancer.253,254

Exosomes play critical roles in various types of disease, and particularly in cancer progression and resistance to therapy. The unique biogenesis of exosomes and their biological features have generated excitement for their potential use as biomarkers for cancer.255 Generally, exosomes are produced and secreted by most cells and contain all the biological components of a cell. Hence, exosomes are found in all biological fluids and provide excellent opportunities for use as biomarkers.242 Surface proteins of exosomes are involved in the regulation of the tumor immune microenvironment and the monitoring of immunotherapies. Hence, exosome proteins play a critical role in cancer signaling.256 Exosomes from patients with metastatic pancreatic cancer show a higher mutant Kras allele frequency than exosomes from patients with local disease. In addition, the exosomes also accumulate a significantly higher level of cancer cell-specific DNA such as cytoplasmic DNA.8,257 Exosomes protect DNA and RNA from enzymatic degradation by encapsulation and stability in exosomes. The enhanced stability and retention of exosomes in liquid biopsies increases the availability and performance of exosomes as cancer biomarkers.258 Cancer cells contain cargo molecules, such as nucleic acid, proteins, metabolites, and lipids that are relatively different from normal cells, which is a contributing factor for their candidacy as cancer biomarkers. Exosomes isolated and purified from patient plasma samples enriched for miR-10b-5p, miR-101-3p, and miR-143-5p have been identified as potential diagnostic markers for gastric cancer with lymph node metastasis, gastric cancer with ovarian metastasis, and gastric cancer with liver metastasis, respectively.259 Kato et al analyzed the expression of CD44 protein and mRNA from cell lysates and exosomes from prostate cancer cells.260 Exosomes from serum containing CD44v8-10 mRNA was used as a diagnostic marker for docetaxel resistance in prostate cancer patients. The study was performed to evaluate plasma exosomal mRNA-125a-5p and miR-141-5p miRNAs as biomarkers for the diagnosis of prostate cancer from 19 healthy individuals and 31 prostate cancer patients. In comparing the miR-125a-5p/miR-141-5p level ratio, prostate cancer patients had significantly higher levels of miR-125a-5p/miR-141-5p. The findings from this study demonstrated that plasma exosomal expression of miR-141-3p and miR-125a-5p are markers of specific tumor traits associated with prostate cancer.261 Serum samples from 81 patients with gastric cancer showed that exosomes contained significant levels of long non-coding RNA (lncRNA) H19, which could be a diagnostic marker for gastric cancer.262 Plasma exosomes are suitable candidates as biomarkers for various diseases. For instance, plasma exosome lncRNA expression profiles were examined in esophageal squamous cell carcinoma (ESCC) patients. The findings suggest that five different types of lncRNAs were at significantly higher levels in exosomes from ESCC patients than in non-cancer controls. These lncRNAs may serve as highly effective, noninvasive biomarkers for ESCC diagnosis.263 Differential expression of lncRNAs, such as LINC00462, HOTAIR, and MALAT1, are significantly upregulated in hepatocellular carcinoma (HCC) tissues. The exosomes of the control group had a larger number of lncRNAs with a high amount of alternative splicing compared to hepatic disease patients.264 To demonstrate exosomes as a non-invasive cancer diagnostic tool, RNA-sequencing analysis was performed between three pairs of non-small-cell lung cancer (NSCLC) patients and controls from Chinese populations. The results show that circ_0047921, circ_0056285, and circ_0007761 were significantly expressed and that these exosomal circRNAs are promising biomarkers for NSCLC diagnosis.265 Exosomes were isolated from the serum of 34 patients with acute myocardial infarction (AMI), 31 patients with unstable angina (UA), and 22 healthy controls. The isolated exosomes exhibited higher levels of miR-126 and miR-21 in the patients with UA and AMI than in the healthy controls.266 Xu et al designed a study to examine tumor-derived exosomes as diagnostic biomarkers. In this study exosome miRNA microarray analysis was performed in the peripheral blood from four lung adenocarcinoma patients, including two with metastasis and two without metastasis. The results found that miR-4436a and miR-4687-5p were upregulated in the metastasis and non-metastasis group, while miR-22-3p, miR-3666, miR-4448, miR-4449, miR-6751-5p, and miR-92a-3p were downregulated. Exosomes containing miR-4448 have served as a diagnostic marker of patients with adenocarcinoma metastasis. Increased understanding of exosome biogenesis, structure, and function would enhance the performance of biomarkers in various kinds of disease diagnosis, prognosis, and surveillance.267

Exosomes have unique features such as ease of handling, molecular composition, and critical immunogenicity, and it is particularly easy to use them to transfer genes and proteins into cells. These unique characteristic features can inhibit angiogenesis and cancer metastasis, which are the two main targets of cancer therapy.268,269 Exosomes have potential therapeutic applications in a variety of diseases due to their potential capacity as vehicles for the delivery of therapeutic agents (Figure 5). Exosomes from colon cancer cells contain the highly immunogenic antigens MelanA/Mart-1 and gp100, serving as an indicator of tumor origin in particular organelles. Animal studies have demonstrated that tumor-derived antigen-containing exosomes induce potent antitumor T-cell responses and tumor regression.270 Exosomes containing tumor antigens are able to stimulate CD4+and CD8+T cells, and antigen-presenting exosomes inhibit tumor growth.135,271,272 MSC-derived exosomes exhibit the immunomodulatory and cytoprotective activities of their parent cells.273,274 Similarly, exosomes derived from bone marrow show protective roles in myocardial ischemia/reperfusion injury,109 hypoxia-induced pulmonary hypertension,275 and brain injury,276,277 and inhibit breast cancer growth via vascular endothelial growth factor down-regulation and miR-16 transfer in mice.278 Mesenchymal cell- and epithelial cell-derived exosomes exhibit tolerance and without any undesired side effects in patients and also act as therapeutic agents themselves.48,279 Exosomes engineered with ligands containing RGD peptide are used to induce signaling in specific cell types, and doxorubicin-loaded exosomes derived from dendritic cells show therapeutic responses in mammary tumor-bearing mice.46 Exosomal microRNAs are able to control other cells, and the delivery of miRNA or siRNA payload promotes anticancer activity in mammary carcinoma and glioma.280,281 Rabies virus glycoprotein (RVG)-modified dendritic cell-derived exosomes suppress the expression of BACE1 in the brain, which indicates the therapeutic potential of exosomes to target AD.282 Furthermore, these exosomes stimulated neurite outgrowth in cultured astrocytes by transferring miR-133b between cells.27 Immunotherapy is able to induce tumor-targeting immunity or an antitumor host immune response. For example, tumor-associated antigen-loaded mature autologous dendritic cells increase survival of metastatic castration-resistant patients.283 Exosome therapy induces upregulation of CD122 molecules in CD4+ T cells, whereas the lymphocyte pool is stable. Multiple vaccinations with exosomes increase circulating CD3-/CD56+ natural killer (NK) cells.284 An in vitro study demonstrated that adipose stem cell-derived exosomes up-regulate the peroxisome proliferator-activated receptor gamma coactivator 1, phosphorylate the cyclic AMP response element binding protein, and ameliorate abnormal apoptotic protein levels.285 Exosomes are used as potential carriers to carry anti-inflammatory drugs. Curcumin-encapsulated exosomes show significant anti-inflammatory activity, and exosomes are also used to deliver anti-inflammatory drugs to the brain through a noninvasive intranasal route.286,287 Turturici et al reported that specific progenitor cell-derived EVs contain biological cargo that promotes angiogenesis and tissue repair, and modulates immune functions.288

Figure 5 Therapeutic potential and versatile clinical implications of exosomes.

Generally, exosomes serve as vehicles for the delivery of drugs and are also actively involved as therapeutic agents. Conversely, injected exosomes enter into other cells and deliver functional cargo molecules very efficiently and rapidly, with minimal immune clearance and are well tolerated.16,21,245,289,290 Intravenous administration of human MSC-derived exosomes supports neuroprotection in a swine model of traumatic brain injury.291 In vitro and in vivo models demonstrate that exosomes from human-induced pluripotent stem cell-derived mesenchymal stromal Cells (hiPSC-MSCs) protect the liver against hepatic ischemia/reperfusion injury through increasing the level of proliferation of primary hepatocytes, activity of sphingosine kinase, and synthesis of sphingosine-1-phosphate (S1P).292 Exosomes derived from macrophages show potential for use in neurological diseases because of their easy entry into the brain by crossing the blood-brain barrier (BBB). Catalase-loaded exosomes displayed a neuroprotective effect in a mouse model of PD and exosomes loaded with dopamine entered into the brain better in comparison to free dopamine.33,293 Treatment of tumor-bearing mice with autologous exosomes loaded with gemcitabine significantly suppressed tumor growth and increase longevity, and caused only minimal damage to normal tissues. The study demonstrated that autologous exosomes are safe and effective vehicles for targeted delivery of GEM against pancreatic cancer.294

Generally, lipid-based nanoparticles such as liposomes or micelles, or synthetic delivery systems have been adopted to transport active molecules. However, the merits of synthetic systems are limited due to various factors including inefficiency, cytotoxicity and/or immunogenicity. Therefore, the development of natural carrier systems is indispensable. One of the most prominent examples of such natural carriers are exosomes, which are used to transport drug and active biomolecules. Exosomes are more compatible with other cells because they carry various targeting molecules from their cells of origin. Exosomes are nano-sized membrane vesicles derived from almost all cell types, which carry a variety of cargo molecules from their parent cells to other cells. Due to their natural biogenesis and unique qualities, including high biocompatibility, enhanced stability, and limited immunogenicity, they have advantages as drug delivery systems (DDSs) compared to traditional synthetic delivery vehicles. For instance, extracellular vesicles, including exosomes, carry and protect a wide array of nucleic acids and can potentially deliver these into recipient cells.6 EVs possess inherent targeting properties due to their lipid composition and protein content enabling them to cross biological barriers, and these salient features exploit endogenous intracellular trafficking mechanisms and trigger a response upon uptake by recipient cells.45,295297 The lipid composition and protein content of exocytic vesicles have specific tropism to specific organs.296 The integrin of exosomes determines the ability to alter the pharmacokinetics of EVs and increase their accumulation in various type of organs including brain, lungs, or liver.117 For example, EVs containing Tspan8 in complex with integrin alpha4 were shown to be preferentially taken up by pancreatic cells.298 Similarly, the lipid composition of EVs influences the cellular uptake of EVs by macrophages.299 EVs derived from dendritic cell achieved targeted knockdown by fusion between expression of Lamp2b and neuron-specific RVG peptide by using siRNA in neuronal cell.45 EVs loaded with Cre recombinase protein were able to deliver functional CreFRB to recipient cells through active and passive mechanisms in the presence of endosomal escape, enhancing the compounds chloroquine and UNC10217832A.300 EVs from cardiosphere-derived cells achieved targeted delivery by fusion of the N-terminus of Lamp2b to a cardiomyocyte-specific peptide (CMP).301 RVG-exosomes were used to deliver anti-alpha-synuclein shRNA minicircle (shRNA-MC) therapy to the alpha-synuclein preformed-fibril-induced mouse model of parkinsonism. This therapy decreased alpha-synuclein aggregation, reduced the loss of dopaminergic neurons, and improved clinical symptoms. RVG exosome-mediated therapy prolonged the effectiveness and was specifically delivered into the brain.302 Zhang et al evaluated the effects of umbilical cord-derived macrophage exosomes loaded with cisplatin on the growth and drug resistance of ovarian cancer cells. High loading efficiency of cisplatin was achieved by membrane disruption of exosomes by sonication.303 Incorporation of cisplatin into umbilical cord blood-derived M1 macrophage exosomes increased cytotoxicity 3.3-fold in drug-resistant A2780/DDP cells and 1.4-fold in drug-sensitive A2780 cells, compared to chemotherapy alone. Loading of cisplatin into M2 exosomes increased cytotoxicity by nearly 1.7-fold in drug-resistant A2780/DDP cells and 1.4-fold in drug-sensitive A2780 cells. The findings suggest that cisplatin-loaded M1 exosomes are potentially powerful tools for the delivery of chemotherapeutics to treat cancers regardless of drug resistance. Shandilya et al developed a chemical-free and non-mechanical method for the encapsulation and intercellular delivery of siRNA using milk-derived exosomes through conjugation between bovine lactoferrin with poly-L-lysine, wherein lactoferrin as a ligand was captured by the GAPDH present in exosomes, loading siRNA in an effortless manner.304 Targeted drug delivery was achieved with low immunogenicity and toxicity using exosomes derived from immature dendritic cells (imDCs) from BALB/c mice by expressing the fusion protein RGD. Recombinant methioninase (rMETase) was loaded into tumor-targeting iRGD-Exos. The findings suggest that the iRGD-Exos-rMETase group exhibited significant antitumor activity compared to the rMETase group.305 Several diseases show high inflammatory responses; therefore, amelioration of inflammatory responses is a critical factor. The inflammatory responses in various disease models can be attenuated through introduction of super-repressor IB (srIB), which is the dominant active form of IB, and can inhibit translocation of nuclear factor B into the nucleus. Intraperitoneal injection of purified srIB-loaded exosomes (Exo-srIBs) showed diminished mortality and systemic inflammation in septic mouse models.306 Systemic administration of macrophage-derived exosomes modified with azide and conjugated with dibenzocyclooctyne-modified antibodies of CD47 and SIRP (aCD47 and aSIRP) through pH-sensitive linkers can actively and specifically target tumors through distinguishing between aCD47 and CD47 on the tumor cell surface.307 SPION-decorated exosomes prepared using fusion proteins of cell-penetrating peptides (CPP) and TNF- (CTNF-)-anchored exosomes coupled with superparamagnetic iron oxide nanoparticles (CTNF--exosome-SPIONs) significantly enhanced tumor cell growth inhibition via induction of the TNFR I-mediated apoptotic pathway. Furthermore, in vivo studies in murine melanoma subcutaneous cancer models showed that TNF--loaded exosome-based vehicle delivery enhanced cancer targeting under an external magnetic field and suppressed tumor growth with mitigating toxicity.308 Yu et al309 developed a formulation of erastin-loaded exosomes labeled with folate (FA) to form FA-vectorized exosomes loaded with erastin (erastin@FA-exo) to target triple-negative breast cancer (TNBC) cells with overexpression of FA receptors. Erastin@FA-exo increased the uptake efficiency of erastin and also significantly inhibited the proliferation and migration of MDA-MB-231 cells compared with erastin@exo and free erastin. Interestingly, erastin@FA-exo promoted ferroptosis with intracellular depletion of glutathione and ROS generation. Plasma exosomes (Exo) loaded with quercetin (Exo-Que) improved the drug bioavailability, enhanced the brain targeting of Que and potently ameliorated cognitive dysfunction in okadaic acid (OA)-induced AD mice compared to free quercetin by inhibiting phosphorylated tau-mediated neurofibrillary tangles.310 Spinal cord injury (SCI) causes paralysis of the limbs. To determine the role of resveratrol in SCI, exosomes derived from resveratrol-treated primary microglia were used as carriers which are able to enhance the solubility of resveratrol and enhance penetration of the drug through the BBB, thereby increasing its concentration in the CNS. The findings demonstrated that Exo + Res are highly effective at crossing the BBB with good stability, suggesting they have potential for enhancing targeted drug delivery and recovering neuronal function in SCI therapy, and is likely associated with the induction of autophagy and inhibition of apoptosis via the PI3K signaling pathway.311 Delivery of miR-204-5p by exosomes inhibits cancer cell proliferation and tumor growth, and induces apoptosis and chemoresistance by specifically suppressing the target genes of miR-204-5p in human cancer cells.312 Engineered exosomes with RVG peptide on the surface for neuron targeting and NGF-loaded exosomes (NGF@ExoRVG) were efficiently delivered into ischemic cortex, with a burst release of encapsulated NGF protein and de novo NGF protein translated from the delivered mRNA. The delivered NGF protein showed high stability and a long retention time, and also reduced inflammation by reshaping microglia polarization, promoted cell survival, and increased the population of double cortin-positive cells, a neuroblast marker.313 Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of AD by activation of microglia cells and increased dendritic spine density.314 Exosome-encapsulated paclitaxel showed efficacy in the treatment of multi-drug resistant cancer cells and it overcomes MDR in cancer cells.315,316 Saari et al found that the loading of Paclitaxel to autologous prostate cancer cell-derived EVs increased its cytotoxic effect.316 Exosome loaded doxorubicin (exoDOX) avoids undesired and unnecessary heart toxicity by partially limiting the crossing of DOX through the myocardial endothelial cells.317 Studies from in vitro and in vivo demonstrate that exosome loaded doxorubicin showed that exosomes did not decrease the efficacy of DOX and there is no cardiotoxicity in DOX-treated mice.318

The intrinsic properties of exosomes have been exploited to control various types of diseases, including neurodegenerative conditions and cancer, through promoting or restraining the delivery of proteins, metabolites, and nucleic acids into recipient cells effectively, eventually altering their biological response. Furthermore, exosomes can be engineered to deliver diverse therapeutic payloads to the target site, including siRNAs, antisense oligonucleotides, chemotherapeutic agents, and immune modulators. The natural lipid and protein composition of exosomes increases bioavailability and minimizes undesirable side effects to the recipients. Due to the availability of exosomes in biological fluid, they can be easily used as potential biomarkers for diagnosis of diseases. Exosomes are naturally decorated with numerous ligands on the surface that can be beneficial for preferential tumor targeting.282 Due to their unique properties, including superior targeting capabilities and safety profile, exosomes are the subject of clinical trials as cancer therapeutic agents.284 Exosomes derived from DCs loaded with tumor antigens have been used to vaccinate cancer patients with the goal of enhancing anti-tumor immune responses.284,319,320

Due to the potential level of various types of cargoes and salient features, exosomes are involved in intercellular messaging and disease diagnosis. As a result of dedicated studies, exosomes have been identified as natural drug delivery vehicles. However, we still face challenges regarding the purity of exosomes due to the lack of standardized techniques for their isolation and purification, inefficient separation methods, difficulties in characterization, and lack of specific biomarkers.321 The first challenge is the use of conventional methods, which are laborious for isolation and purification, time consuming, and vulnerable to contamination by other impurities, which will affect drug delivery processes. The second challenge is the various cellular origins of exosomes, which could affect specific applications. For example, in the application of exosomes in cancer therapy, we should avoid the use of exosomes derived from cancer cells, due to their oncogenic properties. Finally, exosomes have variable properties due to extraction from different types of cell and different cell culture techniques. Therefore, there is a necessity to address and overcome the challenges. There is also a need for an exosome consortium to develop common protocols for the development of rapid and precise methods of exosome isolation, and to assist the selection of sources that are dependent upon the specific therapeutic application. The most important challenge of exosome biology is the clinical translation of exosome-based research using different cell sources. Further characterization studies based on therapeutic applications are needed. Finally, important steps need to be taken to purify exosomes in a feasible, rapid, cost-effective, and scalable manner, which are free from downstream processing and have minimal processing times, that are specifically targeted to therapeutic applications and clinical settings.

The achievement of exosome therapy is based on success rate of clinical trials. Exosomes with size ranges from 60 to 200nm have been used as an active pharmaceutical ingredient or drug carrier in disease treatment. Exosomes derived from human and plant-derived exosomes are registered in clinical trials, but more complete reports are available for humanderived exosomes.322 There are two major exosomes from DCs and MSCs are frequently used in clinical trials, which potentially induce inflammation response and inflammation treatment. The more crucial aspect of exosomes in clinical trials needs to comply with good manufacturing practice (GMP) including upstream, downstream and quality control. Recently, France and USA conducted clinical trials using EVs containing MHCpeptide complexes derived from dendritic could alter tumor growth in immune competent mice and a Phase I anti-non-small cell lung cancer319,320 and several other clinical trial studies are shown in Table 1. Recent clinical case shows promising results with MSC-EVs derived from unrelated bone marrow donors for the treatment of a steroid-refractory graft-vs-host disease patient.279 Similarly, exosomes were used for the treatment of various types of diseases such as melanoma, non-small-cell-lung cancer, colon cancer and chronic kidney disease.284,319,320,323,324

Table 1 Summary of the Exosome Used in Clinical Trials (Source: clinicaltrials.com)

Exosomes are nano-sized membrane vesicles released by the fusion of an organelle of the endocytic pathway, a multivesicular body, with the plasma membrane. Since the last decade, exosomes have played a critical role in nanomedicine and studies related to exosome biology have increased immensely. Exosomes are secreted by almost all cell types and they are found in almost all types of body fluids. They function as mediators of cell-cell communications and play a significant role in both physiological and pathological processes. Exosomes carry a wide range of cargoes including proteins, lipids, RNAs, and DNA, which mediate signaling to recipient cells or tissues, making them a promising diagnostic biomarker and therapeutic tool for the treatment of cancers and other pathologies. In this review, we summarized what is known to date about the factors involved in exosome biogenesis and the role of exosomes in intercellular signaling and cell-cell communications, immune responses, cellular homeostasis, autophagy, and infectious diseases. Further, we reviewed the role of exosomes as diagnostic markers, and their therapeutic and clinical implications. Furthermore, we highlighted the challenges and outstanding developments in exosome research. The clinical application of exosomes is inevitable and they represent multicomponent biomarkers for several diseases including cancer and neurological diseases, etc. Recently, the mortality rate due to various types of cancers has increased. Therefore, therapies are essential to reduce mortality rates. At this juncture, we need sensitive, rapid, cost-effective, and large-scale production of exosomes to use as cancer biomarkers in diagnosis, prognosis, and surveillance. Furthermore, novel technologies are required for further tailoring exosomes as drug delivery vesicles with high drug pay loads, high specificity and low immunogenicity, and free of toxicity undesired side-effects. In addition, standardized and uniform protocols are necessary to isolate and purify exosomes for clinical applications, and more precise isolation and characterization procedures are required to increase understanding of the heterogeneity of exosomes, their cargo, and functions. There is an urgent need for information regarding the composition and mechanisms of action of the various substances in exosomes and to determine how to obtain highly purified exosomes at the right dosage for their clinical use. Currently, exosomes represent a promising tool in the field of nanomedicine and may provide solutions to a variety of todays medical mysteries.

The future direction of exosome research must focus on addressing the differential responses of communication between normal cells and cancer cells, how normal cells rapidly become cancerous, and how exosomes plays critical role in cancer progression via cell-cell communications. In vivo studies need to urgently address the critical factors such as biogenesis, trafficking, and cellular entry of exosomes originating from unmanipulated exosomes that control regulatory pathological functions. Further studies are required to decipher the mechanism of the cell-specific secretion and transport of exosomes, and the biological controls exerted by target cells. Exosomes represent a clinically significant nanoplatform. To substantiate this idea, numerous systematic in vivo studies are necessary to demonstrate the potency and toxicology of exosomes, which could help bring this novel idea a step closer to clinical reality. The most vital part of the system is to optimize the conditions for the engineering of exosomes that are non-toxic, for use in clinical trials. Furthermore, the translation of exosomes into clinical therapies requires their categorization as active drug components or drug delivery vehicles. Finally, future research should focus on the nanoengineering of exosomes that are tailored specifically for drug delivery and clinical efficacy.

Although we are the authors of this review, we would never have been able to complete it without the great many people who have contributed to the field of exosomes biogenesis, functions, therapeutic and clinical implications of exosomes aspects. We owe our gratitude to all those researchers who have made this review possible. We have cited as many references as permitted and apologize to the authors of those publications that we have not cited due to the limitation of references. We apologize to other authors who have worked on these aspects but whom we have unintentionally overlooked.

This study was supported by the KU-Research Professor Program of Konkuk University.

This work was supported by a grant from the Science Research Center (2015R1A5A1009701) of the National Research Foundation of Korea.

The authors report no conflicts of interest related to this work..

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bluebird bio Announces Temporary Suspension on Phase 1/2 and Phase 3 Studies of LentiGlobin Gene Therapy for Sickle Cell Disease (bb1111) – BioSpace

By daniellenierenberg

Feb. 16, 2021 12:00 UTC

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- bluebird bio, Inc. (Nasdaq: BLUE) announced today that the company has placed its Phase 1/2 (HGB-206) and Phase 3 (HGB-210) studies of LentiGlobin gene therapy for sickle cell disease (SCD) (bb1111) on a temporary suspension due to a reported Suspected Unexpected Serious Adverse Reaction (SUSAR) of acute myeloid leukemia (AML).

In line with the clinical study protocols for HGB-206 and HGB-210, bluebird bio placed the studies on temporary suspension following a report received last week that a patient who was treated more than five years ago in Group A of HGB-206 was diagnosed with AML. The company is investigating the cause of this patients AML in order to determine if there is any relationship to the use of BB305 lentiviral vector in the manufacture of LentiGlobin gene therapy for SCD. In addition, a second SUSAR of myelodysplastic syndrome (MDS) in a patient from Group C of HGB-206 was reported last week to the company and is currently being investigated.

No cases of hematologic malignancy have been reported in any patient who has received treatment with betibeglogene autotemcel for transfusion-dependent -thalassemia (licensed as ZYNTEGLOTM in the European Union and the United Kingdom), however because it is also manufactured using the same BB305 lentiviral vector used in LentiGlobin gene therapy for SCD, the company has decided to temporarily suspend marketing of ZYNTEGLO while the AML case is assessed.

The safety of every patient who has participated in our studies or is treated with our gene therapies is the utmost priority for us, said Nick Leschly, chief bluebird. We are committed to fully assessing these cases in partnership with the healthcare providers supporting our clinical studies and appropriate regulatory agencies. Our thoughts are with these patients and their families during this time.

The independent safety review board monitoring the companys studies as well as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have been advised of these cases and bluebird bio will continue to work with regulatory agencies to complete its investigation.

Investor Conference Call Information

bluebird bio will hold a conference call to discuss this update on Tuesday, February 16 at 8:00 a.m. ET. Investors may listen to the call by dialing (844) 825-4408 from locations in the United States or +1 (315) 625-3227 from outside the United States. Please refer to conference ID number 880-6406.

To access the live webcast of bluebird bios presentation, please visit the Events & Presentations page within the Investors & Media section of the bluebird bio website at http://investor.bluebirdbio.com. A replay of the webcast will be available on the bluebird bio website for 90 days following the event.

About HGB-206 and HGB-210

HGB-206 is an ongoing, Phase 1/2 open-label study designed to evaluate the efficacy and safety of LentiGlobin gene therapy for sickle cell disease (SCD) that includes three treatment cohorts: Groups A, B and C. A refined manufacturing process designed to increase vector copy number (VCN) and further protocol refinements made to improve engraftment potential of gene-modified stem cells were used for Group C. Group C patients also received LentiGlobin for SCD made from HSCs collected from peripheral blood after mobilization with plerixafor, rather than via bone marrow harvest, which was used in Groups A and B of HGB-206.

HGB-210 is an ongoing Phase 3 single-arm open-label study designed to evaluate the efficacy and safety of LentiGlobin gene therapy for SCD in patients between two years and 50 years of age with sickle cell disease.

About LentiGlobin for SCD (bb1111)

LentiGlobin gene therapy for sickle cell disease (bb1111) is an investigational treatment being studied as a potential treatment for SCD. bluebird bios clinical development program for LentiGlobin for SCD includes the completed Phase 1/2 HGB-205 study, the ongoing Phase 1/2 HGB-206 study, and the ongoing Phase 3 HGB-210 study.

The U.S. Food and Drug Administration granted orphan drug designation, fast track designation, regenerative medicine advanced therapy (RMAT) designation and rare pediatric disease designation for LentiGlobin for SCD.

LentiGlobin for SCD received orphan medicinal product designation from the European Commission for the treatment of SCD, and Priority Medicines (PRIME) eligibility by the European Medicines Agency (EMA) in September 2020.

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-307) for people who have participated in bluebird bio-sponsored clinical studies of LentiGlobin for SCD. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT04628585 for LTF-307.

LentiGlobin for SCD is investigational and has not been approved in any geography.

About ZYNTEGLO (betibeglogene autotemcel)

Betibeglogene autotemcel (beti-cel) is a one-time gene therapy that adds functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once a patient has the A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived adult Hb, at levels that may eliminate or significantly reduce the need for transfusions. In studies of beti-cel, transfusion independence (TI) is defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average Hb of at least 9 g/dL.

The European Commission granted conditional marketing authorization (CMA) for beti-cel, marketed as ZYNTEGLO gene therapy, for patients 12 years and older with transfusion-dependent -thalassemia (TDT) who do not have a 0/0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen (HLA)-matched related HSC donor is not available.

Non-serious adverse events (AEs) observed during clinical studies that were attributed to beti-cel included abdominal pain, thrombocytopenia, leukopenia, neutropenia, hot flush, dyspnea, pain in extremity, tachycardia and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to beti-cel.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.

For details, please see the Summary of Product Characteristics (SmPC).

On April 28, 2020, the European Medicines Agency (EMA) renewed the CMA for beti-cel. The CMA for beti-cel is valid in the 27 member states of the EU as well as the UK, Iceland, Liechtenstein and Norway.

The U.S. Food and Drug Administration granted beti-cel Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT. Beti-cel is not approved in the U.S. Beti-cel continues to be evaluated in the ongoing Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies.

bluebird bio is conducting a long-term safety and efficacy follow-up study, LTF-303 for people who have participated in bluebird bio-sponsored clinical studies of ZYNTEGLO.

About bluebird bio, Inc.

bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene and cell therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders: cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma, using gene and cell therapy technologies including gene addition, and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash.; Durham, N.C.; and Zug, Switzerland. For more information, visit bluebirdbio.com.

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

ZYNTEGLO, betibeglogene autotemcel, beti-cel, and bluebird bio are trademarks of bluebird bio, Inc.

Forward-Looking Statements

This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the Companys timing and expectations regarding its investigation of the relationship of the AML and MDS events to the use of lentiviral vector BB305 in LentiGlobin gene therapy for SCD, and any myeloablation regimen used in connection with treatment. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements, many of which are beyond the Companys control. These risks and uncertainties include, but are not limited to: the risk that the Company may not be able to definitively determine whether the lentiviral vector BB305 used in LentiGlobin gene therapy for SCD and in betibeglogene autotemcel is related to the patients AML in a timely manner, or at all; the risk that the lentiviral vector BB305 has caused insertional oncogenic events, including AML; the risk that insertional oncogenic events associated with lentiviral vector or additional MDS events associated with myeloablation will be discovered or reported over time; the risk that regulatory authorities may impose a clinical hold, in addition to our temporary clinical hold on the HGB-206 and HGB-210 studies, or on additional programs; the risk that we may not be able to address regulatory authorities concerns quickly or at all; the risk that we may not resume patient treatment with ZYNTEGLO in the commercial context in a timely manner or at all; the risk that our lentiviral vector platform across our severe genetic disease programs may be implicated, affecting the development and potential approval of elivaldogene autotemcel; the risk that we may not be able to execute on our business plans, including our commercialization plans, meeting our expected or planned regulatory milestones, submissions, and timelines, research and clinical development plans, and in bringing our product candidates to market; and the risk that with the impact on the execution and timing of our business plans, we may not successfully execute our previously announced plans to spin off our oncology programs into an independent publicly-traded entity. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in our most recent Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210216005442/en/

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bluebird bio Announces Temporary Suspension on Phase 1/2 and Phase 3 Studies of LentiGlobin Gene Therapy for Sickle Cell Disease (bb1111) - BioSpace

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Beti-Cel Gene Therapy Frees Patients With Beta-Thalassemia From Red Blood Cell Transfusions – OncLive

By daniellenierenberg

Betibeglogene autotemcel (beti-cel), a one-time gene therapy, enabled durable transfusion independence in most patients with transfusion-dependent -thalassemia (TDT) who were treated across 4 clinical studies.

Of 60 patients enrolled overall, 17 of 22 (77%) treated in the 2 phase 1/2 studies were able to stop packed red blood cell transfusions. In the 2 phase 3 studies, which used a refined manufacturing process resulting in improved beti-cel characteristics, 89% (n = 31/35) of patients with at least 6 months of follow-up achieved transfusion independence for more than 6 months,1 reported Suradej Hongeng, MD, during the virtual 2021 Transplantation & Cellular Therapy Meetings.

The median follow-up after beti-cel infusion in the 4 studies has been 24.8 months (range, 1.1-71.8).

With up to 6 years of follow-up, 1-time beti-cel gene therapy enabled durable transfusion independence in the majority of patients, said Hongeng, from Ramathibodi Hospital of Mahidol University, in Bangkok, Thailand.

Patients who achieved transfusion independence experienced a 38% median reduction in liver iron concentration (LIC) from baseline to month 48. The median reduction in LIC was 59% in patients with a baseline LIC more than 15 mg/g dw. A total of 21 of 37 (57%) patients who achieved transfusion independence have stopped iron chelation for 6 months or longer, with a median duration of 18.5 months from stopping iron chelation to last follow-up.

Erythropoiesis as determined by soluble transferrin receptor level was also improved in transfusion-independent patients. Bone marrow biopsies showed improvement in the myeloid:erythroid ratio.

Beti-cel adds functional copies of a modified form of the -globin (A-T87Q-globin) gene into a patients own hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells using a BB305 lentiviral vector. Following single-agent busulfan myeloablative conditioning, beti-cel is infused, after which the transduced HSCs engraft and reconstitute red blood cells containing functional adult hemoglobin derived from the gene therapy.

Of the 60 patients treated, 43 were genotype non-/ and 17 were / . The median age at consent was 20 years in the phase 1/2 trials and 15 years in the phase 3 trials. Median LIC at baseline was 7.1 and 5.5 mg Fe/g dw, respectively, and median cardiac T2 was 34 and 37 msec, respectively. The vector copy number was 0.8 in the phase 1/2 trial and 3.0 in the phase 3 study. Additionally, 32t and 78t CD34+ cells were transduced, respectively.

The phase 1/2 studies showed promising results but lower achievement of transfusion independence in patients with the / genotype, leading to a refinement in the manufacturing process, which resulted in a higher number of transduced cells and a higher number of vector copy number, said Hongeng.

The median time to neutrophil engraftment was 22.5 days and the median time to platelet engraftment was 44 days. Lymphocyte subsets were generally within the normal range after beti-cel infusion, which is different from allogeneic stem cell [transplantation], which is probably around 6 months to a year to get complete recovery of immune reconstitution, he said. The median duration of hospitalization was 42 days.

All patients were alive at the last follow-up (March 3, 2020). Eleven of 60 (18%) of patients experienced at least 1 adverse event (AE) considered related or possibly related to beti-cel, the most common being abdominal pain (8%) and thrombocytopenia (5%). Serious AEs were those expected after myeloablative conditioning: veno-occlusive liver disease (8%), neutropenia (5%), pyrexia (5%), thrombocytopenia (5%), and appendicitis, febrile neutropenia, major depression, and stomatitis (3% each).

Of the 7 patients experiencing veno-occlusive liver disease, 3 were of grade 4 and 2 were of grade 3. Two other patients had grade 2 veno-occlusive disease. There were no cases of insertional oncogenesis.

Persistent vector-positive hematopoietic cells and durable HbaT87Q levels supported stable total hemoglobin over time. In phase 3 trials, the median peripheral blood vector copy number was 1.2 c/dg at month 12 and 2.0 c/dg at month 24, and the median total hemoglobin was 11.5 g/dL at month 12 and 12.9 g/dL at month 24.

The weighted average of hemoglobin during transfusion independence in the phase 1/2 trials was 10.4 g/dL, and patients were transfusion-independent for a median of 51.2 months. In the phase 3 studies, the weighted average of hemoglobin during transfusion independence was 11.9 g/dL, and patients were transfusion-independent for a medium 17.7 months.

Hongeng S, Thompson AA, Kwiatkowski JL, et al. Efficacy and safety of betibeglogene autotemcel (beti-cel; LentiGlobin for -thalassemia) gene therapy in 60 patients with transfusion-dependent -thalassemia (TDT) followed for up to 6 years post-infusion. Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; virtual. Abstract 1.

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Beti-Cel Gene Therapy Frees Patients With Beta-Thalassemia From Red Blood Cell Transfusions - OncLive

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Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease – Science

By daniellenierenberg

Machine learning for medicine

Small-molecule screens aimed at identifying therapeutic candidates traditionally search for molecules that affect one to several outputs at most, limiting discovery of true disease-modifying drugs. Theodoris et al. developed a machine-learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell disease model of a common form of heart disease involving the aortic valve. Gene network correction by the most efficacious therapeutic candidate generalized to primary aortic valve cells derived from more than 20 patients with sporadic aortic valve disease and prevented aortic valve disease in vivo in a mouse model.

Science, this issue p. eabd0724

Determining the gene-regulatory networks that drive human disease allows the design of therapies that target the core disease mechanism rather than merely managing symptoms. However, small molecules used as therapeutic agents are traditionally screened for their effects on only one to several outputs at most, from which their predicted efficacy on the disease as a whole is extrapolated. In silico correlation of disease network dysregulation with pathways affected by molecules in surrogate cell types is limited by the relevance of the cell types used and by not directly testing compounds in patient cells.

In principle, mapping the architecture of the dysregulated network in disease-relevant cells differentiated from patient-derived induced pluripotent stem cells (iPSCs) and subsequent screening for small molecules that broadly correct the abnormal gene network could overcome this obstacle. Specifically, targeting normalization of the core regulatory elements that drive the disease process, rather than correction of peripheral downstream effectors that may not be disease modifying, would have the greatest likelihood of therapeutic success. We previously demonstrated that haploinsufficiency of NOTCH1 can cause calcific aortic valve disease (CAVD), the third most common form of heart disease, and that the underlying mechanism involves derepression of osteoblast-like gene networks in cardiac valve cells. There is no medical therapy for CAVD, and in the United States alone, >100,000 surgical valve replacements are performed annually to relieve obstruction of blood flow from the heart. Many of these occur in the setting of a congenital aortic valve anomaly present in 1 to 2% of the population in which the aortic valve has two leaflets (bicuspid) rather than the normal three leaflets (tricuspid). Bicuspid valves in humans can also be caused by NOTCH1 mutations and predispose to early and more aggressive calcification in adulthood. Given that valve calcification progresses with age, a medical therapy that could slow or even arrest progression would have tremendous impact.

We developed a machine-learning approach to identify small molecules that sufficiently corrected gene network dysregulation in NOTCH1-haploinsufficient human iPSC-derived endothelial cells (ECs) such that they classified similar to NOTCH1+/+ ECs derived from gene-corrected isogenic iPSCs. We screened 1595 small molecules for their effect on a signature of 119 genes representative of key regulatory nodes and peripheral genes from varied regions of the inferred NOTCH1-dependent network, assayed by targeted RNA sequencing (RNA-seq). Overall, eight molecules were validated to sufficiently correct the network signature such that NOTCH1+/ ECs classified as NOTCH1+/+ by the trained machine-learning algorithm. Of these, XCT790, an inverse agonist of estrogen-related receptor (ERR), had the strongest restorative effect on the key regulatory nodes SOX7 and TCF4 and on the network as a whole, as shown by full transcriptome RNA-seq.

Gene network correction by XCT790 generalized to human primary aortic valve ECs derived from explanted valves from >20 patients with nonfamilial CAVD. XCT790 was effective in broadly restoring dysregulated genes toward the normal state in both calcified tricuspid and bicuspid valves, including the key regulatory nodes SOX7 and TCF4.

Furthermore, XCT790 was sufficient to prevent as well as treat already established aortic valve disease in vivo in a mouse model of Notch1 haploinsufficiency on a telomere-shortened background. XCT790 significantly reduced aortic valve thickness, the extent of calcification, and echocardiographic signs of valve stenosis in vivo. XCT790 also reduced the percentage of aortic valve cells expressing the osteoblast transcriptional regulator RUNX2, indicating a reduction in the osteogenic cell fate switch underlying CAVD. Whole-transcriptome RNA-seq in treated aortic valves showed that XCT790 broadly corrected the genes dysregulated in Notch1-haploinsufficient mice with shortened telomeres, and that treatment of diseased aortic valves promoted clustering of the transcriptome with that of healthy aortic valves.

Network-based screening that leverages iPSC and machine-learning technologies is an effective strategy to discover molecules with broadly restorative effects on gene networks dysregulated in human disease that can be validated in vivo. XCT790 represents an entry point for developing a much-needed medical therapy for calcification of the aortic valve, which may also affect the highly related and associated calcification of blood vessels. Given the efficacy of XCT790 in limiting valve thickening, the potential for XCT790 to alter the progression of childhood, and perhaps even fetal, valve stenosis also warrants further study. Application of this strategy to other human models of disease may increase the likelihood of identifying disease-modifying candidate therapies that are successful in vivo.

A gene networkbased screening approach leveraging human disease-specific iPSCs and machine learning identified a therapeutic candidate, XCT790, which corrected the network dysregulation in genetically defined iPSC-derived endothelial cells and primary aortic valve endothelial cells from >20 patients with sporadic aortic valve disease. XCT790 was also effective in preventing and treating a mouse model of aortic valve disease.

Mapping the gene-regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine-learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell (iPSC) disease model of a common form of heart disease involving the aortic valve (AV). Gene network correction by the most efficacious therapeutic candidate, XCT790, generalized to patient-derived primary AV cells and was sufficient to prevent and treat AV disease in vivo in a mouse model. This strategy, made feasible by human iPSC technology, network analysis, and machine learning, may represent an effective path for drug discovery.

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Energy drinks may damage the heart, researchers warnshould the FDA get involved? – Cardiovascular Business

By daniellenierenberg

Drinking certain energy drinks may cause significant damage to the heart, according to new findings published in Food and Chemical Toxicology.

Because the consumption of these beverages is not regulated and they are widely accessible over the counter to all age groups, the potential for adverse health effects of these products is a subject of concern and needed research, lead researcher Ivan Rusyn, MD, PhD, a professor at Texas A&M University in College Station, said in a prepared statement.

Rusyn et al. assessed a total of 17 popular energy drinks, studying their chemical profiles and looking for any associations with potential cardiac complications. Energy drinks sold by Adrenaline, Shoc, Bang Star, C4, CELSIUS, HEAT, EBOOST, Game Fuel, GURU, Kill Cliff, Kickstart, Monster Energy, Red Bull, Reign, Rockstar, RUNA, UPTIME, Venom Energy and Xyience Energy were all part of the teams analysis.

Overall, the authors found that stem cell-derived cardiomyocyteshuman heart cells grown in a laboratoryshowed signs of an increased beat rate after being exposed to some energy drinks. Also, theophylline, adenine and azelate were all ingredients the team associated with potentially contributing to QT prolongation in cardiomyocytes.

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Energy drinks may damage the heart, researchers warnshould the FDA get involved? - Cardiovascular Business

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Outlook on the Cell Therapy Global Market to 2027 – Opportunity Analysis and Industry Forecasts – Yahoo Finance

By daniellenierenberg

Dublin, Feb. 09, 2021 (GLOBE NEWSWIRE) -- The "Cell Therapy Market by Cell Type, Therapy Type, Therapeutic Area, and End User: Global Opportunity Analysis and Industry Forecast, 2020-2027" report has been added to ResearchAndMarkets.com's offering.

The global cell therapy market accounted for $7,754. 89 million in 2019, and is expected to reach $48,115. 40 million by 2027, registering a CAGR of 25. 6% from 2020 to 2027.

Cell therapy involves administration of somatic cell preparations for treatment of diseases or traumatic damages. Cell therapy aims to introduce new, healthy cells into a patient's body to replace diseased or missing ones.

This is attributed to the fact that specialized cells, such as brain cells, are difficult to obtain from human body. In addition, specialized cells typically have a limited ability to multiply, making it difficult to produce sufficient number of cells required for certain cell therapies. Some of these issues can be overcome through the use of stem cells. In addition, cells such as blood and bone marrow cells, mature, immature & solid tissue cells, adult stem cells, and embryonic stem cells are widely used in cell therapy procedures.

Moreover, transplanted cells including induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), neural stem cells (NSCs), and mesenchymal stem cells (MSCs) are divided broadly into two main groups including autologous cells and non-autologous cells. Development of precision medicine and advancements in Advanced Therapies Medicinal Products (ATMPS) in context to their efficiency and manufacturing are expected to be the major drivers for the market. Furthermore, automation in adult stem cells and cord blood processing and storage are the key technological advancements that fuel growth of the market for cell therapy.

In addition, growth in aging patient population, The rise in cell therapy transplantations globally, and surge in disease awareness drive growth of the global cell therapy market. Furthermore, The rise in adoption of human cells over animal cells for cell therapeutics research, technological advancements in field of cell therapy, and increase in incidences of diseases such as cancer, cardiac abnormalities, and organ failure are the key factors that drive growth of the global market.

Moreover, implementation of stringent government regulations regarding the use of cell therapy is anticipated to restrict growth of the market. On the contrary, surge in number of regulations to promote stem cell therapy and increase in funds for research in developing countries are expected to offer lucrative opportunities to the market in the future.

The global cell therapy market is categorized on the basis of therapy type, therapeutic area, cell type, end user, and region. On the basis of therapy type, the market is segregated into autologous and allogenic. By therapeutics, it is classified into malignancies, musculoskeletal disorders, autoimmune disorders, dermatology, and others.

The global cell therapy market is categorized on the basis of therapy type, therapeutic, cell type, end user and region. On the basis of therapy type, the market is segregated into autologous and allogenic. By therapeutic area, it is classified into malignancies, musculoskeletal disorders, autoimmune disorders, dermatology, and others. On the basis of cell type, it is segregated into stem cell therapy and non-stem cell type. On the basis of end user, it is segregated into hospital & clinics and academic & research institutes. On the basis of region, the market is studied across North America, Europe, Asia-Pacific, and LAMEA.

Key Benefits

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The study provides an in-depth analysis of the global cell therapy market along with the current trends and future estimations to elucidate the imminent investment pockets.

Comprehensive analysis of factors that drive and restrict the market growth is provided in the report.

Comprehensive quantitative analysis of the industry from 2019 to 2027 is provided to enable the stakeholders to capitalize on the prevailing market opportunities.

Extensive analysis of the key segments of the industry helps in understanding the forms and types of cell therapy used across the globe.

Key market players and their strategies have been analyzed to understand the competitive outlook of the market.

Key Topics Covered:

Chapter 1: Introduction1.1. Report Description1.2. Key Benefits for Stakeholders1.3. Key Market Segments1.4. Research Methodology1.4.1. Secondary Research1.4.2. Primary Research1.4.3. Analyst Tools & Models

Chapter 2: Executive Summary2.1. Key Findings of the Study2.2. Cxo Perspective

Chapter 3: Market Overview3.1. Market Definition and Scope3.2. Key Findings3.2.1. Top Player Positioning3.2.2. Top Investment Pockets3.2.3. Top Winning Strategies3.3. Porter'S Five Forces Analysis3.4. Impact Analysis3.4.1. Drivers3.4.1.1. Technological Advancements in the Field of Cell Therapy3.4.1.2. The Rise in Number of Cell Therapy Clinical Studies3.4.1.3. The Rise in Adoption of Regenerative Medicine3.4.2. Restraint3.4.2.1. Developing Stage and Pricing3.4.3. Opportunity3.4.3.1. High Growth Potential in Emerging Markets3.5. Impact of Covid-19 on Cell Therapy Market

Chapter 4: Cell Therapy Market, by Cell Type4.1. Overview4.1.1. Market Size and Forecast4.2. Stem Cell4.2.1. Key Market Trends and Opportunities4.2.2. Market Size and Forecast, by Region4.2.3. Market Size and Forecast, by Type4.2.3.1. Bone Marrow, Market Size and Forecast4.2.3.2. Blood, Market Size and Forecast4.2.3.3. Umbilical Cord-Derived, Market Size and Forecast4.2.3.4. Adipose-Derived Stem Cell, Market Size and Forecast4.2.3.5. Others (Placenta, and Nonspecific Cells), Market Size and Forecast4.3. Non-Stem Cell4.3.1. Key Market Trends and Opportunities4.3.2. Market Size and Forecast, by Region

Chapter 5: Cell Therapy Market, by Therapy Type5.1. Overview5.1.1. Market Size and Forecast5.2. Autologous5.2.1. Key Market Trends and Opportunities5.2.2. Market Size and Forecast, by Region5.2.3. Market Analysis, by Country5.3. Allogeneic5.3.1. Key Market Trends and Opportunities5.3.2. Market Size and Forecast, by Region5.3.3. Market Analysis, by Country

Chapter 6: Cell Therapy Market, by Therapeutic Area6.1. Overview6.1.1. Market Size and Forecast6.2. Malignancies6.2.1. Market Size and Forecast, by Region6.2.2. Market Analysis, by Country6.3. Musculoskeletal Disorders6.3.1. Market Size and Forecast, by Region6.3.2. Market Analysis, by Country6.4. Autoimmune Disorders6.4.1. Market Size and Forecast, by Region6.4.2. Market Analysis, by Country6.5. Dermatology6.5.1. Market Size and Forecast, by Region6.5.2. Market Analysis, by Country6.6. Others6.6.1. Market Size and Forecast, by Region6.6.2. Market Analysis, by Country

Chapter 7: Cell Therapy Market, by End-user7.1. Overview7.1.1. Market Size and Forecast7.2. Hospitals & Clinics7.2.1. Key Market Trends and Opportunities7.2.2. Market Size and Forecast, by Region7.2.3. Market Analysis, by Country7.3. Academic & Research Institutes7.3.1. Key Market Trends and Opportunities7.3.2. Market Size and Forecast, by Region7.3.3. Market Analysis, by Country

Chapter 8: Cell Therapy Market, by Region8.1. Overview8.2. North America8.3. Europe8.4. Asia-Pacific8.5. LAMEA

Chapter 9: Company Profiles9.1. Allosource9.1.1. Company Overview9.1.2. Company Snapshot9.1.3. Operating Business Segments9.1.4. Product Portfolio9.1.5. Key Strategic Moves and Developments9.2. Cells for Cells9.2.1. Company Overview9.2.2. Company Snapshot9.2.3. Operating Business Segments9.2.4. Product Portfolio9.3. Holostem Terapie Avanzate Srl9.3.1. Company Overview9.3.2. Company Snapshot9.3.3. Operating Business Segments9.3.4. Product Portfolio9.4. Jcr Pharmaceuticals Co. Ltd.9.4.1. Company Overview9.4.2. Company Snapshot9.4.3. Operating Business Segments9.4.4. Product Portfolio9.4.5. Business Performance9.4.6. Key Strategic Moves and Developments9.5. Kolon Tissuegene, Inc.9.5.1. Company Overview9.5.2. Company Snapshot9.5.3. Operating Business Segments9.5.4. Product Portfolio9.5.5. Key Strategic Moves and Developments9.6. Medipost Co. Ltd.9.6.1. Company Overview9.6.2. Company Snapshot9.6.3. Operating Business Segments9.6.4. Product Portfolio9.6.5. Business Performance9.7. Mesoblast Ltd9.7.1. Company Overview9.7.2. Company Snapshot9.7.3. Operating Business Segments9.7.4. Product Portfolio9.7.5. Business Performance9.8. Nuvasive, Inc.9.8.1. Company Overview9.8.2. Company Snapshot9.8.3. Operating Business Segments9.8.4. Product Portfolio9.8.5. Business Performance9.9. Osiris Therapeutics, Inc.9.9.1. Company Overview9.9.2. Company Snapshot9.9.3. Operating Business Segments9.9.4. Product Portfolio9.10. Stemedica Cell Technologies, Inc.9.10.1. Company Overview9.10.2. Company Snapshot9.10.3. Operating Business Segments9.10.4. Product Portfolio

For more information about this report visit https://www.researchandmarkets.com/r/bja7iz

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Autologous Stem Cell Based Therapies Market Global Expansion by Key Segments and Industry Dynamics From 2021 to 2026 Atlantic Financial Management -…

By daniellenierenberg

According to the new market research report Autologous Stem Cell Based Therapies Market Strategic recommendations, Trends, Segmentation, Use Case Analysis, Competitive Intelligence, Global and Regional Forecast (to 2026), published by In4Research, acknowledges you about the market developments, technological advancements, supply & demand scenario, pricing factors, and emerging trends that are going to influence the growth of the Autologous Stem Cell Based Therapies market. This research report also provides details on the revenue drivers, product innovations, government regulations & policies that act as a game-changer in the market growth.

The report provides insights on the following pointers:

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The report also contains brief information on the key players in the Autologous Stem Cell Based Therapies industry operating on the Market. The report provides in-depth information on the industry overview, the share of revenues, developments, mergers and acquisitions, and key strategies. The report also includes a full analysis of product innovation and consumer behavior. The Autologous Stem Cell Based Therapies market has been segmented by commodity type, end-users, technology, industry verticals, and regions. The in-depth research will allow readers to better understand well-established and emerging players in shaping their business strategies to achieve long-term and short-term goals. The report outlines a wide range of areas and locations where key participants could identify opportunities for the future.

The Major Players Covered in Autologous Stem Cell Based Therapies Market Report are:

Application Analysis: Global Autologous Stem Cell Based Therapies market also specifically underpins end-use application scope and their improvements based on technological developments and consumer preferences.

Product Type Analysis: Global Autologous Stem Cell Based Therapies market also specifically underpins type scope and their improvements based on technological developments and consumer preferences.

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The report is a versatile reference guide to understand developments across multiple regions such as depicted as under:

In this study, the years considered to estimate the market size of Autologous Stem Cell Based Therapies Market:

In the report, the market outlook section mainly encompasses fundamental dynamics of the market which include drivers, restraints, opportunities, and challenges faced by the industry. Drivers and restraints are intrinsic factors whereas opportunities and challenges are extrinsic factors of the Autologous Stem Cell Based Therapies Market.

In4Research narrows down the available data using primary sources to validate the data and use it in compiling a full-fledged market research study. The report contains a quantitative and qualitative estimation of market elements that interest the client. The Global Autologous Stem Cell Based Therapies Market is mainly bifurcated into sub-segments which can provide classified data regarding the latest trends in the market.

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Chapters Covered in Autologous Stem Cell Based Therapies Market Report are As Follow:

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Autologous Stem Cell Based Therapies Market Global Expansion by Key Segments and Industry Dynamics From 2021 to 2026 Atlantic Financial Management -...

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Engineered stem cells that evade immune detection could …

By daniellenierenberg

Sana Biotechnology was founded in 2018 with a mission of solving some of the most difficult challenges in gene and cell therapy. Toward that end, the company is engineering hypoimmune stem cells that can evade detection and destruction by the immune system.

Now, some of Sanas founders, who are scientists at the University of California, San Francisco (UCSF), are describing how these engineered stem cells are able to shut down the immune systems natural killer (NK) cells. They believe their findings could enhance the development of implantable cell therapies, as well as cancer immunotherapies, they reported in the Journal of Experimental Medicine.

The ability to evade NK cells could enhance a range of experimental treatments, including implants of insulin-producing cells for patients with diabetes and cardiac cells to repair heart damage. These cells are typically rejected by the immune systema problem hypoimmune stem cells were designed to circumvent.

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The UCSF team used gene modification technology to design the cells so they avoid the immune responses that are either built into the bodys defense system or learned. The researchers achieved that feat by engineering the cells to express the protein CD47, which shuts down innate immune cells by activating signal regulatory protein alpha, or SIRP-alpha.

The researchers were surprised to discover that the hypoimmune stem cells were able to escape NK cells, even though NK cells were not previously known to express SIRP-alpha. Rather than studying lab-grown cell lines, they took cells directly from patients. Thats where they found SIRP-alpha.

Whats more, the UCSF team discovered that NK cells begin to express SIRP-alpha after they are activated by cytokines that are typically abundant in inflammatory states.

RELATED: Fierce Biotech's 2020 Fierce 15 | Sana Biotechnology

To further prove out the utility of engineered stem cells, the UCSF researchers implanted cells with rhesus macaque CD47 into monkeys. They documented the activation of SIRP-alpha in NK cells. Those NK cells did not kill the transplanted cells.

A similar technique could be used, but in reverse, to implant pig cardiac cells into people, the UCSF team argued. If human CD47 were engineered into pig heart cells, they could be implanted into people without risking rejection by NK cells, they suggested.

Sana made waves in 2018 when it raised a whopping $700 million in a single venture round from the likes of Arch Venture Partners, Flagship Pioneering and Bezos Expeditions. We believe that one of, if not the most, important thing happening in medicine over the next several decades is the ability to modulate genes, use cells as medicines, and engineer cells, said Steve Harr, president and CEO of Sana, at the time.

Sana did not provide materials or funding for the new study, but it is now developing the hypoimmune stem cell technology for clinical testing.

The UCSF team believes their findings could also boost cancer immunotherapy. The engineered cells could help combat checkpoints that allow tumors to evade immune detection, they said.

"Many tumors have low levels of self-identifying MHC-I protein and some compensate by overexpressing CD47 to keep immune cells at bay," said Lewis Lanier, Ph.D., director of the Parker Institute for Cancer Immunotherapy at the UCSF Helen Diller Family Comprehensive Cancer Center, in a statement. "This might be the sweet spot for antibody therapies that target CD47."

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Worldwide Cell Therapy Industry to 2027 – Profiling Allosource, Medipost and Mesoblast Among Others – PRNewswire

By daniellenierenberg

DUBLIN, Feb. 9, 2021 /PRNewswire/ -- The "Cell Therapy Market by Cell Type, Therapy Type, Therapeutic Area, and End User: Global Opportunity Analysis and Industry Forecast, 2020-2027" report has been added to ResearchAndMarkets.com's offering.

The global cell therapy market accounted for $7,754. 89 million in 2019, and is expected to reach $48,115. 40 million by 2027, registering a CAGR of 25. 6% from 2020 to 2027.

Cell therapy involves administration of somatic cell preparations for treatment of diseases or traumatic damages. Cell therapy aims to introduce new, healthy cells into a patient's body to replace diseased or missing ones.

This is attributed to the fact that specialized cells, such as brain cells, are difficult to obtain from human body. In addition, specialized cells typically have a limited ability to multiply, making it difficult to produce sufficient number of cells required for certain cell therapies. Some of these issues can be overcome through the use of stem cells. In addition, cells such as blood and bone marrow cells, mature, immature & solid tissue cells, adult stem cells, and embryonic stem cells are widely used in cell therapy procedures.

Moreover, transplanted cells including induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), neural stem cells (NSCs), and mesenchymal stem cells (MSCs) are divided broadly into two main groups including autologous cells and non-autologous cells. Development of precision medicine and advancements in Advanced Therapies Medicinal Products (ATMPS) in context to their efficiency and manufacturing are expected to be the major drivers for the market. Furthermore, automation in adult stem cells and cord blood processing and storage are the key technological advancements that fuel growth of the market for cell therapy.

In addition, growth in aging patient population, The rise in cell therapy transplantations globally, and surge in disease awareness drive growth of the global cell therapy market. Furthermore, The rise in adoption of human cells over animal cells for cell therapeutics research, technological advancements in field of cell therapy, and increase in incidences of diseases such as cancer, cardiac abnormalities, and organ failure are the key factors that drive growth of the global market.

Moreover, implementation of stringent government regulations regarding the use of cell therapy is anticipated to restrict growth of the market. On the contrary, surge in number of regulations to promote stem cell therapy and increase in funds for research in developing countries are expected to offer lucrative opportunities to the market in the future.

The global cell therapy market is categorized on the basis of therapy type, therapeutic area, cell type, end user, and region. On the basis of therapy type, the market is segregated into autologous and allogenic. By therapeutics, it is classified into malignancies, musculoskeletal disorders, autoimmune disorders, dermatology, and others.

The global cell therapy market is categorized on the basis of therapy type, therapeutic, cell type, end user and region. On the basis of therapy type, the market is segregated into autologous and allogenic. By therapeutic area, it is classified into malignancies, musculoskeletal disorders, autoimmune disorders, dermatology, and others. On the basis of cell type, it is segregated into stem cell therapy and non-stem cell type. On the basis of end user, it is segregated into hospital & clinics and academic & research institutes. On the basis of region, the market is studied across North America, Europe, Asia-Pacific, and LAMEA.

Key Benefits

Key Topics Covered:

Chapter 1: Introduction1.1. Report Description1.2. Key Benefits for Stakeholders1.3. Key Market Segments1.4. Research Methodology1.4.1. Secondary Research1.4.2. Primary Research1.4.3. Analyst Tools & Models

Chapter 2: Executive Summary2.1. Key Findings of the Study2.2. Cxo Perspective

Chapter 3: Market Overview3.1. Market Definition and Scope3.2. Key Findings3.2.1. Top Player Positioning3.2.2. Top Investment Pockets3.2.3. Top Winning Strategies3.3. Porter's Five Forces Analysis3.4. Impact Analysis3.4.1. Drivers3.4.1.1. Technological Advancements in the Field of Cell Therapy3.4.1.2. The Rise in Number of Cell Therapy Clinical Studies3.4.1.3. The Rise in Adoption of Regenerative Medicine3.4.2. Restraint3.4.2.1. Developing Stage and Pricing3.4.3. Opportunity3.4.3.1. High Growth Potential in Emerging Markets3.5. Impact of Covid-19 on Cell Therapy Market

Chapter 4: Cell Therapy Market, by Cell Type4.1. Overview4.1.1. Market Size and Forecast4.2. Stem Cell4.2.1. Key Market Trends and Opportunities4.2.2. Market Size and Forecast, by Region4.2.3. Market Size and Forecast, by Type4.2.3.1. Bone Marrow, Market Size and Forecast4.2.3.2. Blood, Market Size and Forecast4.2.3.3. Umbilical Cord-Derived, Market Size and Forecast4.2.3.4. Adipose-Derived Stem Cell, Market Size and Forecast4.2.3.5. Others (Placenta, and Nonspecific Cells), Market Size and Forecast4.3. Non-Stem Cell4.3.1. Key Market Trends and Opportunities4.3.2. Market Size and Forecast, by Region

Chapter 5: Cell Therapy Market, by Therapy Type5.1. Overview5.1.1. Market Size and Forecast5.2. Autologous5.2.1. Key Market Trends and Opportunities5.2.2. Market Size and Forecast, by Region5.2.3. Market Analysis, by Country5.3. Allogeneic5.3.1. Key Market Trends and Opportunities5.3.2. Market Size and Forecast, by Region5.3.3. Market Analysis, by Country

Chapter 6: Cell Therapy Market, by Therapeutic Area6.1. Overview6.1.1. Market Size and Forecast6.2. Malignancies6.2.1. Market Size and Forecast, by Region6.2.2. Market Analysis, by Country6.3. Musculoskeletal Disorders6.3.1. Market Size and Forecast, by Region6.3.2. Market Analysis, by Country6.4. Autoimmune Disorders6.4.1. Market Size and Forecast, by Region6.4.2. Market Analysis, by Country6.5. Dermatology6.5.1. Market Size and Forecast, by Region6.5.2. Market Analysis, by Country6.6. Others6.6.1. Market Size and Forecast, by Region6.6.2. Market Analysis, by Country

Chapter 7: Cell Therapy Market, by End-user7.1. Overview7.1.1. Market Size and Forecast7.2. Hospitals & Clinics7.2.1. Key Market Trends and Opportunities7.2.2. Market Size and Forecast, by Region7.2.3. Market Analysis, by Country7.3. Academic & Research Institutes7.3.1. Key Market Trends and Opportunities7.3.2. Market Size and Forecast, by Region7.3.3. Market Analysis, by Country

Chapter 8: Cell Therapy Market, by Region8.1. Overview8.2. North America8.3. Europe8.4. Asia-Pacific8.5. LAMEA

Chapter 9: Company Profiles9.1. Allosource9.1.1. Company Overview9.1.2. Company Snapshot9.1.3. Operating Business Segments9.1.4. Product Portfolio9.1.5. Key Strategic Moves and Developments9.2. Cells for Cells9.2.1. Company Overview9.2.2. Company Snapshot9.2.3. Operating Business Segments9.2.4. Product Portfolio9.3. Holostem Terapie Avanzate Srl9.3.1. Company Overview9.3.2. Company Snapshot9.3.3. Operating Business Segments9.3.4. Product Portfolio9.4. Jcr Pharmaceuticals Co. Ltd.9.4.1. Company Overview9.4.2. Company Snapshot9.4.3. Operating Business Segments9.4.4. Product Portfolio9.4.5. Business Performance9.4.6. Key Strategic Moves and Developments9.5. Kolon Tissuegene, Inc.9.5.1. Company Overview9.5.2. Company Snapshot9.5.3. Operating Business Segments9.5.4. Product Portfolio9.5.5. Key Strategic Moves and Developments9.6. Medipost Co. Ltd.9.6.1. Company Overview9.6.2. Company Snapshot9.6.3. Operating Business Segments9.6.4. Product Portfolio9.6.5. Business Performance9.7. Mesoblast Ltd9.7.1. Company Overview9.7.2. Company Snapshot9.7.3. Operating Business Segments9.7.4. Product Portfolio9.7.5. Business Performance9.8. Nuvasive, Inc.9.8.1. Company Overview9.8.2. Company Snapshot9.8.3. Operating Business Segments9.8.4. Product Portfolio9.8.5. Business Performance9.9. Osiris Therapeutics, Inc.9.9.1. Company Overview9.9.2. Company Snapshot9.9.3. Operating Business Segments9.9.4. Product Portfolio9.10. Stemedica Cell Technologies, Inc.9.10.1. Company Overview9.10.2. Company Snapshot9.10.3. Operating Business Segments9.10.4. Product Portfolio

For more information about this report visit https://www.researchandmarkets.com/r/shw12n

Media Contact:

Research and Markets Laura Wood, Senior Manager [emailprotected]

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Worldwide Cell Therapy Industry to 2027 - Profiling Allosource, Medipost and Mesoblast Among Others - PRNewswire

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Harnessing the Potential of Cell and Gene Therapy – OncLive

By daniellenierenberg

Excitement took wing in the scientific community in the early 1990s, when the first gene therapy trial showed significant success, only to crash at the end of the decade with a patients tragic death.

Twenty years later, the excitement is back and greater than before. Although safety remains a concern, investigators are breaking ground in cell and gene therapy, and many believe that ultimately, a string of cured cancers will follow.

In 2017, the excitement over these therapies returned in spades when the FDA signed off on a cell-therapy drug for the first time, approving the chimeric antigen receptor (CAR) T-cell treatment tisagenlecleucel (Kymriah; Novartis) for patients with B-cell precursor acute lymphoblastic leukemia. At last, scientists had devised a way to reprogram a persons own T cells to attack tumor cells.

Were entering a new frontier, said Scott Gottlieb, MD, then-FDA commissioner, in announcing the groundbreaking approval.

Gottlieb was not exaggerating. The growth in CAR T-cell research is exploding. Although only a handful of cell and gene therapies are on the market, the FDA predicted in 2019 that it will receive more than 200 investigational new drug applications per year for cell and gene therapies, and that by 2025, it expects to have accelerated to 10 to 20 cell and gene therapy approvals per year.

We can absolutely cut the number of cancer deaths down so that one day in our lifetimes it can be a rare thing for people to die of cancer, said Patrick Hwu, MD, president and CEO of Moffitt Cancer Center in Florida and among gene therapys pioneers. It still may happen here and there, but itll be kind of like people dying of pneumonia. Its like, He died of pneumonia? Thats kind of weird. I think cancer can be the same way.

Essentially, you can kill any cancer cell that has an antigen that is recognized by the immune cell, Hwu said. The key to curing every single cancer, which is our goal, is to have receptors that can recognize the tumor but dont recognize the normal cells.

Community oncologists will need to be increasingly familiar about the various products, including their immediate and longer-term risks, Bo Wang, MD, and Deepu Madduri, MD, recently wrote in OncologyLive.1 It is key to understand the optimal time for referring these patients to an academic institution, as well as how to manage the requisite post CAR T-cell therapy in the community setting. Madduri is an assistant professor of medicine, hematology and medical oncology, as well as associate director of cellular therapy service, and director of clinical operations with the Center of Excellence for Multiple Myeloma at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai in New York, New York. Wang is a third-year clinical fellow in hematology/oncology at Mount Sinai.

Early referral to academic centers and hospitals equipped to deliver therapies is crucial for patients eligible for therapy. However, as advances continue in the field, community practices may be called upon to administer therapies in their clinic.

The Community Oncology Alliance (COA) envisions a broader role for the settings in which CAR T-cell therapies can be administered. When the Centers for Medicare & Medicaid Services (CMS) was considering coverage for CAR T-cell therapies in 2019, COA officials argued against limiting approvals to hospitals.

It is important to understand that there are state-of-the-art community oncology practices that have significant experience and capabilities in administering highly complex treatments, COA officials wrote in a letter to CMS. For example, stem cell transplants, which are similar in complexity to CAR T therapy, are performed successfully in the community oncology practice setting.2

Broader use of gene therapies depends on several factors, including navigating the logistics of gene therapies, addressing the high costs, and managing toxicities.3

Autologous CAR T-cell therapies involve a manufacturing process that requires coordination between the treating facility and the processing facility. Following leukapheresis, patients may require maintenance therapy to control disease progression during the manufacturing time, which can take 3 to 5 weeks.

In terms of cost, gene and cell therapies can cost from $375,000 to $475,000 per dose and they may face coverage restrictions from payers. Approvals could take weeks to obtain.3,4

Because of cytokine release syndrome and neurotoxicities associated with CAR T-cell therapy, the FDA mandates risk evaluation and mitigation strategy training for centers.

Further, providers may find that real-world experiences with gene therapies are different from those seen in the clinical trial setting, according to Ankit J. Kansagra, MD.

In a presentation at the 2020 American Society of Clinical Oncology Virtual Education Program, Kansagra, an assistant professor of medicine and Eugene P. Frenkel, MD, Scholar in Clinical Medicine at Harold C. Simmons Comprehensive Cancer Center in Dallas, Texas, said that in practice patients may be older and have more aggressive disease, with double- and triple-hit lymphomas.4

Specifically, Kansagra noted that medications such as steroids and/or tocilizumab (Actemra) to prevent or treat cytokine release syndrome or other toxicities were more frequently used in the real-world setting than what had been seen in clinical trials.

As it stands now, only a fraction of eligible patients are receiving CAR T-cell therapies, Kansagra said. Potentially, 9750 patients a year may be eligible for CAR T-cell therapies in approved and upcoming hematologic indications. From 2016 to 2019, a total of 2058 patients received CAR T-cell infusion.4

Next steps for transplanting these novel therapies to clinical practice will require changes in key areas, Kansagra said, such as supply chain management, patient support, and financial systems (Figure).4

Figure. Next Steps for Effective Delivery of Gene and Cell Therapies4

Meanwhile, multiple myeloma experts advise providers to be ready for change. As commercially available myeloma CAR T-cell therapies are approved, it will be even more important for community oncologists to better understand these therapies so they can offer them to their patients, Wang and Madduri wrote.1

Cell therapy involves cultivating or modifying immune cells outside the body before injecting them into the patient. Cells may be autologous (self-provided) or allogeneic (donor-provided); they include hematopoietic stem cells and adult and embryonic stem cells. Gene therapy modifies or manipulates cell expression. There is considerable overlap between the 2 disciplines.

Juliette Hordeaux, PhD, senior director of translational research for the University of Pennsylvanias gene therapy program, is cautious about the FDAs predictions, saying shed be thrilled with 5 cell and/or gene therapy approvals annually.

For monogenic diseases, there are only a certain number of mutations, and then well plateau until we reach a stage where we can go after more common diseases, Hordeaux said.

Safety has been the main brake around adeno-associated virus vector [AAV] gene therapy, added Hordeaux, whose hospitals program has the institutional memory of both Jesse Gelsingers tragic death during a 1999 gene therapy trial as well as breakthroughs by 2015 Giants of Cancer Care winner in immuno-oncology Carl H. June, MD, and others in CAR T-cell therapy. Sometimes there are unexpected toxicity [events] in trials.I think figuring out ways to make gene therapy safer is going to be the next goal for the field before we can even envision many more drugs approved.

In total, 3 CAR T-cell therapies are now on the market, all targeting the CD19 antigen. Tisagenlecleucel was the first. Gilead Sciences received approval in October 2017 for axicabtagene ciloleucel (axi-cel; Yescarta), a CAR T-cell therapy for adults with large B-cell non-Hodgkin lymphoma. Kite Pharma, a subsidiary of Gilead, received an accelerated approval in July 2020 for brexucabtagene autoleucel (Tecartus) for adults with relapsed/ refractory mantle cell lymphoma.

Another CD19-directed therapy under FDA review for relapsed/refractory large B-cell lymphoma, is lisocabtagene maraleucel (liso-cel; JCAR017; Bristol Myers Squibb). Idecabtagene vicleucel (ide-cel; bb2121; Bristol Myers Squibb) is under priority FDA review, with a decision expected by March 31, 2021. The biologics license application for ide-cel seeks approval for the B-cell maturation antigendirected CAR therapy to treat adult patients with multiple myeloma who have received at least 3 prior therapies.5

The number of clinical trials evaluating CAR T-cell therapies has risen sharply since 2015, when investigators counted a total of 78 studies registered on the ClinicalTrials. gov website. In June 2020, the site listed 671 trials, including 357 registered in China, 256 in the United States, and 58 in other countries.6 Natural killer (NK) cells are the research focus of Dean A. Lee, MD, PhD, a physician in the Division of Hematology and Oncology at Nationwide Childrens Hospital in Columbus, Ohio. He developed a method for consistent, robust expansion of highly active clinical-grade NK cells that enables repeated delivery of large cell doses for improved efficacy. This finding led to several first-in-human clinical trials evaluating adoptive immunotherapy with expanded NK cells under an FDA investigational new drug application. Lee is developing both genetic and nongenetic methods to improve tumor targeting and tissue homing of NK cells. His efforts are geared toward pediatric sarcomas.

The biggest emphasis over the past 20 to 25 years has been cell therapy for cancer, talking about trying to transfer a specific part of the immune system for cells, said Lee, who is also director of the Cellular Therapy and Cancer Immunology Program at Nationwide Childrens Hospital, at The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital, and at the Richard J. Solove Research Institute.

However, Lee said, NKs have wider potential. This is kind of a natural swing back. Now that we know we can grow them, we can reengineer them against infectious disease targets and use them in that [space], he said.

Lee is part of a coronavirus disease 2019 (COVID-19) clinical trial, partnering with Kiadis, for off-the-shelf K-NK cells using Kiadis proprietary platforms. Such treatment would be a postexposure preemptive therapy for treating COVID-19. Lee said the pivot toward treating COVID19 with cell therapy was because some of the very early reports on immune responses to coronavirus, both original [SARS-CoV-2] and the new [mutation], seem to implicate that those who did poorly [overall] had poorly functioning NK cells.

The revolutionary gene editing tool CRISPR is making its initial impact in clinical trials outside the cancer area. Its developers, Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD, won the Nobel Prize in Chemistry 2020.

For patients with sickle cell disease (SCD), CRISPR was used to reengineer bone marrow cells to produce fetal hemoglobin, with the hope that the protein would turn deformed red blood cells into healthy ones. National Public Radio (NPR) did a story on one patient who, so far, thanks to CRISPR, has been liberated from the attacks of SCD that typically have sent her to the hospital, as well from the need for blood transfusions.7

Its a miracle, you know? the patient, Victoria Gray of Forest, Mississippi, told NPR.

She was among 10 patients with SCD or transfusion-dependent beta-thalassemia treated with promising results, as reported by the New England Journal of Medicine.8

Stephen Gottschalk, MD, chair of the department of bone marrow transplantation and cellular therapy at St Jude Childrens Research Hospital, said, Theres a lot of activity to really explore these therapies with diseases that are much more common than cancer.

Animal models use T cells to reverse cardiac fibrosis, for instance, Gottschalk said. Using T cells to reverse pathologies associated with senescence, such as conditions associated with inflammatory clots, are also being studied.

CAR T, I think, will become part of the standard of care, Gottschalk said. The question is how to best get that accomplished. To address the tribulations of some autologous products, a lot of groups are working with off-the-shelf products to get around some of the manufacturing bottlenecks. I believe those issues will be solved in the long run.

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Stem Cell Study Illuminates the Cause of a Devastating Inherited Heart Disorder – Newswise

By daniellenierenberg

Newswise PHILADELPHIAScientists in the Perelman School of Medicine at the University of Pennsylvania have uncovered the molecular causes of a congenital form of dilated cardiomyopathy (DCM), an often-fatal heart disorder.

This inherited form of DCM which affects at least several thousand people in the United States at any one time and often causes sudden death or progressive heart failure is one of multiple congenital disorders known to be caused by inherited mutations in a gene called LMNA. The LMNA gene is active in most cell types, and researchers have not understood why LMNA mutations affect particular organs such as the heart while sparing most other organs and tissues.

In the study, published this week in Cell Stem Cell, the Penn Medicine scientists used stem cell techniques to grow human heart muscle cells containing DCM-causing mutations in LMNA. They found that these mutations severely disrupt the structural organization of DNA in the nucleus of heart muscle cells but not two other cell types studied leading to the abnormal activation of non-heart muscle genes.

Were now beginning to understand why patients with LMNA mutations have tissue-restricted disorders such as DCM even though the gene is expressed in most cell types, said study co-senior author Rajan Jain, MD, an assistant professor of Cardiovascular Medicine and Cell and Developmental Biology at the Perelman School of Medicine.

Further work along these lines should enable us to predict how LMNA mutations will manifest in individual patients, and ultimately we may be able to intervene with drugs to correct the genome disorganization that these mutations cause, said study co-senior author Kiran Musunuru, MD, PhD, a professor of Cardiovascular Medicine and Genetics, and Director of the Genetic and Epigenetic Origins of Disease Program at Penn Medicine.

Inherited LMNA mutations have long puzzled researchers. The LMNA gene encodes proteins that form a lacy structure on the inner wall of the cell nucleus, where chromosomes full of coiled DNA are housed. This lacy structure, known as the nuclear lamina, touches some parts of the genome, and these lamina-genome interactions help regulate gene activity, for example in the process of cell division. The puzzle is that the nuclear lamina is found in most cell types, yet the disruption of this important and near-ubiquitous cellular component by LMNA mutations causes only a handful of relatively specific clinical disorders, including a form of DCM, two forms of muscular dystrophy, and a form of progeria a syndrome that resembles rapid aging.

To better understand how LMNA mutations can cause DCM, Jain, Musunuru, and their colleagues took cells from a healthy human donor, and used the CRISPR gene-editing technique to create known DCM-causing LMNA mutations in each cell. They then used stem cell methods to turn these cells into heart muscle cells cardiomyocytes and, for comparison, liver and fat cells. Their goal was to discover what was happening in the mutation-containing cardiomyocytes that wasnt happening in the other cell types.

The researchers found that in the LMNA-mutant cardiomyocytes but hardly at all in the other two cell types the nuclear lamina had an altered appearance and did not connect to the genome in the usual way. This disruption of lamina-genome interactions led to a failure of normal gene regulation: many genes that should be switched off in heart muscle cells were active. The researchers examined cells taken from DCM patients with LMNA mutations and found similar abnormalities in gene activity.

A distinctive pattern of gene activity essentially defines what biologists call the identity of a cell. Thus the DCM-causing LMNA mutations had begun to alter the identity of cardiomyocytes, giving them features of other cell types.

The LMNA-mutant cardiomyocytes also had another defect seen in patients with LMNA-linked DCM: the heart muscle cells had lost much of the mechanical elasticity that normally allows them to contract and stretch as needed. The same deficiency was not seen in the LMNA-mutant liver and fat cells.

Research is ongoing to understand whether changes in elasticity in the heart cells with LMNA mutations occurs prior to changes in genome organization, or whether the genome interactions at the lamina help ensure proper elasticity. Their experiments did suggest an explanation for the differences between the lamina-genome connections being badly disrupted in LMNA-mutant cardiomyocytes but not so much in LMNA-mutant liver and fat cells: Every cell type uses a distinct pattern of chemical marks on its genome, called epigenetic marks, to program its patterns of gene activity, and this pattern in cardiomyocytes apparently results in lamina-genome interactions that are especially vulnerable to disruption in the presence of certain LMNA mutations.

The findings reveal the likely importance of the nuclear lamina in regulating cell identity and the physical organization of the genome, Jain said. This also opens up new avenues of research that could one day lead to the successful treatment or prevention of LMNA-mutations and related disorders.

Other co-authors of the study were co-first authors Parisha Shah and Wenjian Lv; and Joshua Rhoades, Andrey Poleshko, Deepti Abbey, Matthew Caporizzo, Ricardo Linares-Saldana, Julie Heffler, Nazish Sayed, Dilip Thomas, Qiaohong Wang, Liam Stanton, Kenneth Bedi, Michael Morley, Thomas Cappola, Anjali Owens, Kenneth Margulies, David Frank, Joseph Wu, Daniel Rader, Wenli Yang, and Benjamin Prosser.

Funding was provided by the Burroughs Wellcome Career Award for Medical Scientists, Gilead Research Scholars Award, Pennsylvania Department of Health, American Heart Association/Allen Initiative, the National Institutes of Health (DP2 HL147123, R35 HL145203, R01 HL149891, F31 HL147416, NSF15-48571, R01 GM137425), the Penn Institute of Regenerative Medicine, and the Winkelman Family Fund for Cardiac Innovation.

###

Penn Medicineis one of the worlds leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of theRaymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nations first medical school) and theUniversity of Pennsylvania Health System, which together form a $8.6 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according toU.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.

The University of Pennsylvania Health Systems patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Centerwhich are recognized as one of the nations top Honor Roll hospitals byU.S. News & World ReportChester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nations first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 43,900 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2019, Penn Medicine provided more than $583 million to benefit our community.

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Merck Receives Positive EU CHMP Opinion for Expanded Approval of KEYTRUDA (pembrolizumab) in Certain Patients With Relapsed or Refractory Classical…

By daniellenierenberg

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of an expanded label for KEYTRUDA, Mercks anti-PD-1 therapy. The opinion is recommending KEYTRUDA as monotherapy for the treatment of adult and pediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option.

This recommendation is based on results from the pivotal Phase 3 KEYNOTE-204 trial, in which KEYTRUDA monotherapy demonstrated a significant improvement in progression-free survival (PFS) compared with brentuximab vedotin (BV), a commonly used treatment. KEYTRUDA reduced the risk of disease progression or death by 35% (HR=0.65 [95% CI, 0.48-0.88]; p=0.00271) and showed a median PFS of 13.2 months versus 8.3 months for patients treated with BV. The recommendation is also based on supportive data from an updated analysis of the KEYNOTE-087 trial, which supported the European Commissions (EC) approval of KEYTRUDA for the treatment of adult patients with relapsed or refractory cHL who have failed ASCT and BV or who are transplant ineligible and have failed BV. The CHMPs recommendation will now be reviewed by the EC for marketing authorization in the European Union (EU), and a final decision is expected in the first quarter of 2021. If approved, this will be the first pediatric indication for KEYTRUDA in the EU.

This positive opinion reinforces the importance of KEYTRUDA for certain adult and pediatric patients with relapsed or refractory classical Hodgkin lymphoma in the European Union, said Dr. Vicki Goodman, vice president, clinical research, Merck Research Laboratories. We look forward to the decision by the European Commission and will continue to expand our clinical development program in blood cancers with KEYTRUDA and our recently acquired investigational therapies to help address the unmet needs of patients.

Merck is studying KEYTRUDA across hematologic malignancies through a broad clinical program, including multiple registrational trials in cHL and primary mediastinal large B-cell lymphoma and more than 60 investigator-initiated studies across 15 tumors. In addition to KEYTRUDA, Merck is evaluating two clinical-stage assets for the treatment of patients with hematologic malignancies: MK-1026 (formerly ARQ 531), a Brutons tyrosine kinase inhibitor, and VLS-101, an antibody-drug conjugate targeting ROR1.

About KEYNOTE-204

KEYNOTE-204 (ClinicalTrials.gov, NCT02684292) is a randomized, open-label, Phase 3 trial evaluating KEYTRUDA monotherapy compared with BV for the treatment of patients with relapsed or refractory cHL. The primary endpoints are PFS and overall survival (OS), and the secondary endpoints include objective response rate (ORR), complete remission rate (CRR) and safety. The study enrolled 304 patients, aged 18 years and older, who were randomized to receive either:

About Hodgkin Lymphoma

Hodgkin lymphoma is a type of lymphoma that develops in the white blood cells called lymphocytes, which are part of the immune system. Hodgkin lymphoma can start almost anywhere most often in lymph nodes in the upper part of the body, with the most common sites being in the chest, neck or under the arms. Worldwide, there were approximately 83,000 new cases of Hodgkin lymphoma diagnosed, and more than 23,000 people died from the disease in 2020. In the EU, there were nearly 20,000 new cases of Hodgkin lymphoma diagnosed, and nearly 4,000 people died from the disease in 2020. Classical Hodgkin lymphoma accounts for more than nine in 10 cases of Hodgkin lymphoma in developed countries.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,300 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1). All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

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Merck Receives Positive EU CHMP Opinion for Expanded Approval of KEYTRUDA (pembrolizumab) in Certain Patients With Relapsed or Refractory Classical...

To Read More: Merck Receives Positive EU CHMP Opinion for Expanded Approval of KEYTRUDA (pembrolizumab) in Certain Patients With Relapsed or Refractory Classical…
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Merck Presents Results From Head-to-Head Phase 3 KEYNOTE-598 Trial Evaluating KEYTRUDA (pembrolizumab) in Combination With Ipilimumab Versus KEYTRUDA…

By daniellenierenberg

In KEYNOTE-598, the addition of ipilimumab to KEYTRUDA did not improve overall survival or progression-free survival, and patients who received the combination were more likely to experience serious side effects than those who received KEYTRUDA monotherapy, said Dr. Michael Boyer, chief clinical officer and conjoint chair of thoracic oncology, Chris OBrien Lifehouse, Camperdown, NSW, Australia. KEYTRUDA monotherapy remains a standard of care for the first-line treatment of certain patients with metastatic non-small cell lung cancer whose tumors express PD-L1.

As a leader in lung cancer, we are pursuing a broad clinical program to better understand the potential of KEYTRUDA-based combinations to improve survival outcomes for patients with this devastating disease, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. KEYNOTE-598 is the first head-to-head study designed to answer the question of whether combining KEYTRUDA with ipilimumab provided additional clinical benefits beyond treatment with KEYTRUDA alone in certain patients with metastatic non-small cell lung cancer. The results are clear the combination did not add clinical benefit but did add toxicity.

These results were presented in the Presidential Symposium at the IASLC 2020 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer on Friday, Jan. 29 and published in the Journal of Clinical Oncology. As previously announced in Nov. 2020, the study was discontinued due to futility based on the recommendation of an independent Data Monitoring Committee (DMC), which determined the benefit/risk profile of KEYTRUDA in combination with ipilimumab did not support continuing the trial. The DMC also advised that patients in the study discontinue treatment with ipilimumab/placebo.

KEYNOTE-598 Study Design and Additional Data (Late-Breaking Abstract #PS01.09)

KEYNOTE-598 (ClinicalTrials.gov, NCT03302234) is a randomized, double-blind, Phase 3 trial designed to evaluate KEYTRUDA in combination with ipilimumab compared to KEYTRUDA monotherapy as first-line treatment for patients with metastatic NSCLC without EGFR or ALK genomic tumor aberrations and whose tumors express PD-L1 (TPS 50%). The dual primary endpoints are OS and PFS. Secondary endpoints include objective response rate (ORR), duration of response (DOR) and safety.

The study enrolled 568 patients who were randomized 1:1 to receive KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle for up to 35 cycles) in combination with ipilimumab (1 mg/kg IV on Day 1 of each six-week cycle for up to 18 cycles); or KEYTRUDA (200 mg IV on Day 1 of each three-week cycle for up to 35 cycles) as monotherapy. Non-binding futility criteria for the study were based on restricted mean survival time (RMST), an alternative outcome measure estimated as the area under the survival curve through a fixed timepoint. The pre-specified criteria were differences in RMST for KEYTRUDA in combination with ipilimumab and KEYTRUDA monotherapy of 0.2 at the maximum observation time and 0.1 at 24 months of follow-up.

As of data cut-off, the median study follow-up was 20.6 months. Findings showed the median OS was 21.4 months for patients randomized to KEYTRUDA in combination with ipilimumab (n=284) versus 21.9 months for those randomized to KEYTRUDA monotherapy (n=284) (HR=1.08 [95% CI, 0.85-1.37]; p=0.74). The differences in RMST for KEYTRUDA in combination with ipilimumab and KEYTRUDA monotherapy were -0.56 at the maximum observation time and -0.52 at 24 months, meeting the futility criteria for the trial and confirming the benefit/risk profile of the combination did not support continuing the study. Additionally, the median PFS was 8.2 months for patients randomized to KEYTRUDA in combination with ipilimumab versus 8.4 months for those randomized to KEYTRUDA monotherapy (HR=1.06 [95% CI, 0.86-1.30]; p=0.72). In both arms of the study, ORR was 45.4%; the median DOR was 16.1 months for patients randomized to KEYTRUDA in combination with ipilimumab versus 17.3 months for those randomized to KEYTRUDA monotherapy.

No new safety signals for KEYTRUDA monotherapy were observed. Treatment-related adverse events (TRAEs) occurred in 76.2% of patients treated with KEYTRUDA in combination with ipilimumab versus 68.3% of patients treated with KEYTRUDA monotherapy. Of these TRAEs, 35.1% vs. 19.6% were Grade 3-5, 27.7% vs. 13.9% were serious, 6.0% vs. 3.2% led to discontinuation of ipilimumab or placebo, 19.1% vs. 7.5% led to discontinuation of both drugs and 2.5% vs. 0.0% (no patients) led to death. Additionally, immune-mediated adverse events (AEs) and infusion reactions occurred in 44.7% of patients treated with KEYTRUDA in combination with ipilimumab versus 32.4% of patients treated with KEYTRUDA monotherapy. Of these immune-mediated AEs, 20.2% vs. 7.8% were Grade 3-5, 19.1% vs. 7.1% were serious, 1.8% vs. 1.1% led to discontinuation of ipilimumab or placebo, 12.1% vs. 4.3% led to discontinuation of both drugs and 2.1% vs. 0.0% (no patients) led to death.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon and breast cancers combined. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. Small cell lung cancer (SCLC) accounts for about 10% to 15% of all lung cancers. Before 2014, the five-year survival rate for patients diagnosed in the U.S. with NSCLC and SCLC was estimated to be 5% and 6%, respectively.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,300 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1). All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatments and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

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Elevian Targets Aging to Solve Humanity’s Toughest Diseases – BioSpace

By daniellenierenberg

Mark Allen, CEO of Elevian, pictured above. Photo courtesy of Elevian.

Once the domain of mythical fountains of youth and movies like The Curious Case of Benjamin Button, the science of aging prevention and reversal is beginning to enter the mainstream with reputable academic institutions launching companies to accomplish this once improbable feat.

One such company, Elevian, founded by a team of Harvard scientists and physician-turned entrepreneurDr. Mark Allen, is working to restore regenerative capacity with the aim of preventing and treating age-related diseases. A critical factor, they say, is a single protein called Growth differentiation factor 11 (GDF11).

Allen, Elevians chief executive officer, first became interested in the science of aging after taking a course focused on exponential thinking.

All of a sudden, problems that were heretofore unsolvable become solvable, Allen said of the theory that is the opposite of incremental and encourages one to think outside of the box. They talked about examples of problems that weve always thought to be unsolvable, one of them being aging and longevity. So that was it for me. I was like thats perfect for me. Thats what I want to work on.

Searching for clues into the diseases associated with aging, Elevians founders, including Harvard professor of Stem Cell and Regenerative BiologyDr. Amy Wagers, mined the proteome, looking into how proteins change with age. They uncovered several, including one with potentially groundbreaking regenerative capabilities, GDF11.

Elevian believes that this single protein, a key player in the circulatory system, could be a game-changer in regenerative medicine.

GDF11 is one of those proteins that change with age, Allen said. They [the founders] really dug into GDF11 because so little was known about it at the time of their discoveries. They did side-by-side studies with the parabiosis model, injecting just GDF11, to see if it could reproduce some of the effects of parabiosis in the aged animal. And they found, much to everybodys surprise, that replenishing just this one circulating factor was able to reproduce the beneficial effects of parabiosis.

Parabiosis, which means living beside, is performed by joining two living organisms surgically to develop a single, shared physiology. It has been used to study conjoined twins, and more recently, in a 1972 lifespan study attaching old and young rats, scientists Frederic C. Ludwig and Robert M. Elashoff showed evidence of an extended lifespan for the older animals.

As a post-doc at Harvard, Dr. Wagers expanded upon this research using modern histology techniques. When Wagers and her colleagues attached the circulatory systems of young mice to old ones, they found strong evidence of a biological reversal of cardiac hypertrophy, which occurs with aging. They attributed this to GDF11 in a paper published in Science in 2014 and recognized as a runner-up to the publications Breakthrough of the Year.

What they found is that the old animals exposed to young blood experienced a biological reversal of aging by many different measures. Their brains grow younger, their hearts grow younger, their lungs, their bones all over their body. And interestingly, the young animals exposed to old blood have accelerated aging. So this is just really strong proof that circulating factors regulate aging, said Allen.

The mechanism of action appears to be that GDF11 binds directly to the endothelial projectors, the cells that line our blood vessels and improve both the quality and quantity of the vasculature. It does not cross the blood-brain barrier, so we think its mechanism is primarily by improving vasculature, he explained.

Elevian, the recent beneficiary of an initial round of seed financing, is actioning this potent protein to develop a potential regenerative treatment for stroke patients.

English biomedical gerontologist Aubrey de Grey, whom Allen credits with doing a lot to start the medical field of aging reversal, outlined several hallmarks of aging in his 2007 book, Ending Aging. These include stem cell exhaustion, protein aggregate buildup, failed intercellular communicationand senescent cells.

One of the barriers to developing therapeutics based on these factors is the inherent incongruence with the usual regulatory approval systems. Following customary protocol, proving that a drug prevents aging or age-related diseases would quite literally take a lifetime.

Theres no regulatory path for treating aging. Even doing a prevention trial would take years and years and years, because you have to take people and wait until they get disease to see effects. So instead, to get a drug to market, we take the opposite extreme. We look at what is the most devastating possible disease, unmet need, where we could treat for the shortest possible duration and see clinically meaningful effects, Allen explained.

Elevian decided on stroke, which is the number two cause of death worldwide and the third leading cause of disability.

The only existing treatments for a stroke are limited to the acute phase, where an IV injection of a drug such as recombinant tissue plasminogen activator (tPA) (Activase)restores blood flow by dissolving the clot causing the event.

In an ischemic stroke, which makes up 87% of cases, a blood clot forms and prevents blood and oxygen from reaching an area of the brain, impacting breathing and heart function and often leading to paralysis. This is where Elevian believes a drug utilizing GDF11, which acts on the circulatory system, holds such promise for rehabilitation.

Allen revealed that his team has already demonstrated GDF11s impact on stroke-stricken animals.

When we give GDF11 to animals that have had strokes and are paralyzed or have severe motor function debilitation, it returns them almost to normal function. It significantly improves motor function recovery, he said.

On the strength of these preclinical results, Elevian is gearing up to enter human clinical trials with GDF11 for the treatment of stroke.

We really got the green light to go into humans based upon the animal data that we got there, Allen said, adding that there is still a lot of work to be done before they reach this phase. We still have to scale up production of the drug and we have to do extensive safety and toxicology tests IND-enabling studies. The longest pole in the tent is figuring out how to make manufacturing costs effective. The cost of goods is going to be really, really high. So were doing a lot of work in process development right now, and then were going to hand it off to a manufacturing partner to scale up. Were about two years from initiating our human clinical trial in stroke.

Another unmet need where Elevian believes GDF11 can have an impact is Type 2 diabetes, a disorder whose pathology is also intricately connected to the circulatory system and often to aging.

Along with blood clotting factors, glucose resides within the inside lining of blood vessels. In Type 2 diabetics, the lining of an individuals blood vessels begins to become glycosylated, which causes them to narrow, impeding blood flow. Glucose tolerance is known to decrease with age.

In a study published in March 2020, Wagers and her colleagues stated that GDF11 was shown to significantly improve glucose tolerance in aged mice and increase glucose homeostasis, under a variety of dietary conditions.

Allen believes that addressing the aging process is the ultimate exponential strategy to solving a whole host of humanitys biggest killers:

This idea that we could, by targeting the aging progress, potentially promote healthy aging, promote a healthy longevity, and reduce the burden of age-related diseases, and that the same treatment could be used to treat and prevent multiple age-related diseases. That concept was like, why arent we working on that? Why are we spending billions of dollars on Alzheimers and billions of dollars on cancer, billions of dollars on heart disease? We could instead target the aging process and potentially treat them all.

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Elevian Targets Aging to Solve Humanity's Toughest Diseases - BioSpace

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The Cardiac Rhythm Management Market to undergo an exponential transformation between 2015 and 2021 NeighborWebSJ – NeighborWebSJ

By daniellenierenberg

Cardiac rhythm management refers to a process of monitoring functioning of the heart through devices. Cardiac rhythm management devices are used to provide therapeutic solutions to patients suffering from cardiac disorders such as cardiac arrhythmias, heart failure, and cardiac arrests. Cardiac disorders lead to irregular heartbeat. Technological advancements and rise in the number of deaths due to increasing incidences of heart diseases and increasing aging population are some of the major factors driving the cardiac rhythm management market. Heart disease is one of the primary causes of death in the U. S. Excess of alcohol consumption; smoking, high cholesterol levels, and obesity are some of the major causes of heart diseases. Cardiac rhythm management is conducted through two major devices: implantable cardiac rhythm devices and pacemakers. Implantable cardiac rhythm devices treat patients with an improper heartbeat. Based on the device, the cardiac rhythm management market can be segmented into defibrillators, pacemakers, cardiac resynchronization therapy devices, implantable defibrillators, and external defibrillators. Pacemakers are used to treat patients with a slow heartbeat. Based on the end user, the cardiac rhythm management market can be segmented into hospitals, home/ambulatory, and others.

North America has the largest market for cardiac rhythm management due to improved healthcare infrastructure, government initiatives, rise in incidences of cardiac disorders, growing number of deaths due to cardiovascular diseases,and increasing healthcare expenditure in the region. The North America market for cardiac rhythm management is followed by Europe. Asia is expected to witness high growth rate in the cardiac rhythm management market in the next few years due to increasing incidences of cardiovascular diseases, growing disposable income, rise in awareness regarding heart disorders and relevant treatments, and improving healthcare infrastructure in the region.

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Increasing the prevalence of cardiovascular diseases, technological advancements, rise in life expectancy, increasing awareness regarding cardiac disorders, and government initiatives are some of the major factors that are expected to drive the market for cardiac rhythm management. In addition, factors such as a rise in disposable income, increasing aging population, and high cost associated with heart disease treatment are expected to drive the market for cardiac rhythm management. However, economic downturn, reimbursement issues, the importance of biologics and stem cells, and inappropriate use of the devices are some of the factors restraining the growth of the global cardiac rhythm management market.

Growing population and economies in the developing countries such as India and China are expected to drive the growth of the cardiac rhythm management market in Asia. In addition,factors such as innovations along with technological advancements such as miniaturization, introduction of MRI pacemakers, biocompatible materials and durable batteries, and continuous rise in aging population and increasing cardiovascular diseases such as arrhythmias, stroke, and high blood pressure are expected to create new opportunities for the global cardiac rhythm management market. An increasing number of mergers and acquisitions, rise in the number of collaborations and partnerships, and new product launches are some of the latest trends in the global cardiac rhythm management market.

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Some of the major companies operating in the global cardiac rhythm management market areMedtronic, Abbott Laboratories, Boston Scientific, St. Jude Medical, Altera, and Sorin.Other companies with significant presence in the global cardiac rhythm management market include

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The Cardiac Rhythm Management Market to undergo an exponential transformation between 2015 and 2021 NeighborWebSJ - NeighborWebSJ

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Stem Cells- Definition, Properties, Types, Uses, Challenges

By daniellenierenberg

Biology Educational Videos

Last Updated on October 12, 2020 by Sagar Aryal

Stem cells are unique cells present in the body that have the potential to differentiate into various cell types or divide indefinitely to produce other stem cells.

Figure: Stem Cell Renewal and Differentiation. Image Source: Maharaj Institute of Immune Regenerative Medicine.

All the stem cells found throughout all living systems have three important properties. These properties can be visualized in vitro by a process called clonogenic assays, where a single cell is assessed for its ability to differentiate.

The following are some properties of stem cells:

Figure: Techniques for generating embryonic stem cell cultures. Image Source: John Wiley & Sons, Inc. (Nico Heins et al.)

Depending on the source of the stem cells or where they are present, stem cells are divided into various types;

Figure: Human Embryonic Stem Cells Differentiation. Image created with biorender.com

Figure: Preliminary Evidence of Plasticity Among Nonhuman Adult Stem Cells. Image Source: NIH Stem Cell Information.

Figure: Progress in therapies based on iPSCs. Image Source: Nature Reviews Genetics (R. Grant Rowe & George Q. Daley).

Figure: Mesenchymal stem cells (MSCs). Image Source: PromoCell GmbH.

Some of the common and well-known examples of stem cell research are:

Stem cell research has been used in various areas because of their properties. Some of the common applications of stem cells research include;

Because of different ethical and other issues related to stem cell research, there are some limitations or challenges of stem cell research. Some of these are:

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Stem Cells- Definition, Properties, Types, Uses, Challenges

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