April 1st, 2022

Company Name: Representative:

HEALIOS K.K.

Hardy TS Kagimoto, Chairman & CEO

(TSE Mothers Code: 4593)

Joint Research with the Division of Regenerative Medicine, the Institute of Medical Science for Developing a Mass Production Method of UDC Liver Buds

HEALIOS K.K. ("Healios") is currently developing a regenerative medicine treatment whereby liver organ buds created from iPS cells are injected into the liver and grown into functioning liver tissue, with the aim of improving or restoring the function of a damaged liver (development code: HLCL041). This treatment could potentially replace the need for an organ transplant for certain patients. Liver buds are created by co-culturing liver progenitor cells, which can differentiate into hepatocytes; MSCs, which have the ability to develop into various types of connective-tissues; and vascular endothelial cells, which form blood vessels. Healios has pursued research and generated data on functional assessments and quality standards for these component cells and the liver buds created from them, and it is also proceeding with the development of mass culturing and manufacturing methods.

In addition, as announced on October 20th, 2020, Healios established Universal Donor Cells ("UDCs")*, which are next-generation iPS cells created with gene-editing technology that have a reduced risk of immune rejection regardless of a patient's HLA type, and its proprietary clinical-grade UDC line. We are currently conducting research both internally and through joint collaborations with several institutions on new treatments for diseases for which there is no existing cure.

As part of these efforts, Healios is pleased to announce that it has entered into a joint research agreement with the Division of Regenerative Medicine (Prof. Hideki Taniguchi) of the Institute of Medical Science at the University of Tokyo, to advance HLCL041 utilizing UDCs. In this joint research, we plan to establish a new method for inducing differentiation of liver buds using UDCs and to develop a highly efficient and scalable cell culturing and mass manufacturing system.

For many diseases where the only effective treatment is an organ transplant, Healios believes that organ buds created from iPSCs, which have the potential to restore organ function, hold significant promise as an alternative to organ transplants and as a means to address the perennial shortage of organ donors.

This agreement does not have a material impact on our consolidated financial results for the current fiscal year. We will promptly make an announcement on any matter that requires disclosure in the future.

Outline of the Collaboration Partner

Name of the Collaborator: Division of Regenerative Medicine, The Institute of Medical Science Adress:4-6-1 Shirokanedai Minato-ku, Tokyo, 108-8639, Japan

Representative: Professor Taniguchi Hideki

* UDCs

UDCs are iPS cells created using gene-editing technology that allows them to avoid and / or reduce the body's immune rejection response. The production of Healios' UDCs involve the removal of certain HLA genes that elicit a rejection response, the introduction of an immunosuppression gene to improve immune evasion, and the addition of a suicide gene serving as a safety mechanism, each in an allogeneic iPS cell. This next-generation technology platform allows for the creation of regenerative medicine products with enhanced safety and a lower risk of immune rejection, while preserving the inherent ability of iPS cells to replicate themselves continuously and their pluripotency in differentiating into various other kinds of cells.

About the Division of Regenerative Medicine, The Institute of Medical Science:

Regenerative medicine is a challenging scientific field that is going to convert the pioneering knowledge of developmental biology and stem cell biology to clinical application. For patients with end-stage organ failure, organ transplantation is the only effective treatment; however, the paucity of transplantable organs hinders the application of this treatment for most patients. Recently, regenerative medicine with transplantable organs has attracted attention. Our laboratory is developing a novel therapeutic strategy to substitute organ transplantation. We have established novel organoid culture technologies to reconstruct human organs from stem cells, including human induced pluripotent stem cells (iPSCs), and we are going to realize transplantation of human liver primordia (liver buds [LBs]) generated from iPSCs for the treatment of liver diseases. https://stemcell-imsut.org/laboratory/?id=en#labo1

About Healios:

Healios is Japan's leading clinical stage biotechnology company harnessing the potential of stem cells for regenerative medicine. It aims to offer new therapies for patients suffering from diseases without effective treatment options. Healios is a pioneer in the development of regenerative medicines in Japan, where it has established a proprietary, gene-edited "universal donor" induced pluripotent stem cell (iPSC) line to develop next generation regenerative treatments in immuno-oncology, ophthalmology, liver diseases, and other areas of severe unmet medical need. Healios' lead iPSC-derived cell therapy candidate, HLCN061, is a next generation NK cell treatment for solid tumors that has been functionally enhanced through gene-editing. Its near-term pipeline includes the somatic stem cell product HLCM051, which is currently being evaluated in Japan in Phase 2/3 and Phase 2 trials in ischemic stroke and acute respiratory distress syndrome (ARDS), respectively. Healios was established in 2011 and has been listed on the Tokyo Stock Exchange since 2015 (TSE Mothers: 4593). https://www.healios.co.jp/en .

Contact:

Department of Corporate Communications, HEALIOS K.K.

E-mail:ir@healios.jp

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Healios K K : Joint Research with the Division of Regenerative Medicine, the Institute of Medical Science for Developing a Mass Production Method of...

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Lineage Announces Pipeline Expansion to Include Auditory Neuronal Cell Therapy for Treatment of Hearing Loss - Galveston County Daily News

Spinal Cord Stem Cells Comments Off on Lineage Announces Pipeline Expansion to Include Auditory Neuronal Cell Therapy for Treatment of Hearing Loss – Galveston County Daily News | March 22nd, 2022

All data and statistics are based on publicly available data at the time of publication. Some information may be out of date. Visit our coronavirus hub and follow our live updates page for the most recent information on the COVID-19 pandemic.

A recent study in Nature found subtle changes in the brains of people with mild to moderate COVID-19 after the initial 4 weeks or acute phase of a SARS-CoV-2 infection. The study showed that individuals with SARS-CoV-2 showed greater brain tissue damage and shrinkage of brain regions at an average of 4.5 months after their COVID-19 diagnosis.

Dr. Maxime Taquet, a senior research fellow at the University of Oxford, who was not involved in the study, said: It is well established that [SARS-CoV-2] infection is associated with subsequent risks of neurological and psychiatric problems in some people, including brain fog, loss of taste and smell, depression, and psychosis. But why this occurs remains largely unknown.

This study starts to shed light on this important question by showing that brain regions connected to the smell center of the brain can shrink after COVID-19 in some people.

The studys co-author, Professor Naomi Allen, chief scientist at UK Biobank, noted, [This] is the only study in the world to be able to demonstrate before versus after changes in the brain associated with SARS-CoV-2 infection.

Neurological symptoms are common both during and after the acute phase of a SARS-CoV-2 infection. Previous studies examining changes in the brain underlying these neurological symptoms have mostly focused on people with acute COVID-19.

The small number of studies assessing brain changes after the acute phase of a SARS-CoV-2 infection lacked access to brain imaging data before the infection. Consequently, some of the differences observable in these studies could be due to brain anomalies or risk factors that existed before the infection.

Researchers conducted the present study to distinguish brain anomalies relating to COVID-19 from those that may occur due to preexisting risk factors. Moreover, the study used multiple types of brain scans to assess brain changes in many individuals, facilitating the identification of subtle brain anomalies associated with the SARS-CoV-2 infection.

In the present study, the researchers used data from the UK Biobank, a large database containing medical information, including brain imaging data, from individuals in the United Kingdom.

Specifically, they used imaging data collected from 785 people using different brain scans before and after the onset of the COVID-19 pandemic. This included 401 participants with a SARS-CoV-2 infection between the two scans and 384 control adults without a COVID-19 diagnosis.

The scientists matched participants in the two groups for age, sex, ethnicity, and the duration between the two brain scans. The average duration between the COVID-19 diagnosis and the second set of brain scans was 141 days.

The researchers used software programs to analyze the raw brain imaging data and extract quantifiable features, called image-derived phenotypes (IDPs). Each IDP measures a specific brain structure or function, such as the change in brain region activity while performing a task or the volume of a specific brain structure.

In the present study, the researchers measured changes in over 2,500 IDPs for each individual.

A loss of smell or olfaction is observable in most individuals with a SARS-CoV-2 infection, including after the acute phase. Therefore, the researchers focused on brain regions either directly involved in processing olfactory information or those connected to the olfactory system.

They found a greater reduction in gray matter volume and a greater increase in tissue damage markers in specific brain regions associated with the olfactory system in participants with SARS-CoV-2 compared with controls. The gray matter comprises mainly of cell bodies of nerve cells and is involved in information processing.

There was also a greater loss of gray matter across the entire brain and an increase in the volume of cerebrospinal fluid in participants with a SARS-CoV-2 infection.

In other words, besides changes in brain regions associated with olfaction, there were global changes in the brains of participants with SARS-CoV-2. Notably, these brain anomalies were observable in individuals with mild to moderate COVID-19.

Examining differences in cognitive function, the researchers found that the participants with SARS-CoV-2 showed deficits in executive function, which encompasses higher-level cognitive functions such as thinking, reasoning, and decision-making.

Additionally, there was a correlation between a lower performance in the executive function test and atypical brain changes in a part of the cerebellum known to be involved in cognition.

These findings might help explain why some people experience brain symptoms long after the acute infection. The causes of these brain changes, whether they can be prevented or even reverted, as well as whether similar changes are observed in hospitalized patients, in children and younger adults, and in minority ethnic groups, remain to be determined, said Dr. Taquet.

However, the researchers noted that they did not have data on whether the participants with a SARS-CoV-2 infection had symptoms of long COVID. They were also unable to assess the association between the brain anomalies and potential long COVID symptoms.

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COVID-19: Even mild to moderate infection may cause brain anomalies - Medical News Today

Spinal Cord Stem Cells Comments Off on COVID-19: Even mild to moderate infection may cause brain anomalies – Medical News Today | March 22nd, 2022

With its tail flipping rhythmically from side to side, this strange synthetic fish scoots around in its salt and glucose solution, using the same power as our beating hearts.

This nifty miniaturized circulatory system, developed by scientists at Harvard and Emory universities, can keep swimming to the beat for more than 100 days.

The inventors have high hopes for the strange little device, composed of living heart muscle cells (cardiomyocytes) grown from human stem cells.

The creation of the 'biohybrid' fish focuses on two key regulatory features of our hearts: their ability to function spontaneously, without need for conscious input (automaticity); and messaging initiated by mechanical motion (mechanoelectrical signaling).

This insights learned from the research will hopefully allow researchers to more closely examine these aspects in heart diseases.

"Our ultimate goal is to build an artificial heart to replace a malformed heart in a child," saysHarvard University bioengineer Kevin Kit Parker.

While it's straightforward enough to create something that may look like a heart, making something that actually functions like one is a much harder challenge. The wriggling fishbot is a big step towards this, building on previous work using rat heart muscles to build a jellyfish biohybrid pump and a cyborg stingray.

"I could build a model heart out of Play-Doh, it doesn't mean I can build a heart,"explainsParker.

"You can grow some random tumor cells in a dish until they curdle into a throbbing lump and call it a cardiac organoid. Neither of those efforts is going to, by design, recapitulate the physics of a system that beats over a billion times during your lifetime while simultaneously rebuilding its cells on the fly.

"That is the challenge. That is where we go to work."

With two layers of cardiomyocytes on each side of the tail fin, the biohybrid fish is built to be autonomous it can self-perpetuate its own movement.

When one side squeezes tight, the other side is stretched, triggering a feedback mechanism that causes the stretched side to contract and then trigger the same mechanism on the other side in an ongoing cycle.

This system of asynchronous muscle contractions is based on insect flight muscles.

Each contraction automatically triggers the other muscle pair to contract. (Lee et al., Science, 2022)

The physical bending is the mechanical motion that activates the electrical signal forming ion channels in the muscles. These ion channels trigger the muscles to activate and contract.

Exposing the system to streptomycin and gadoliniumknown to disrupt ion channels in musclesended up decreasing swimming speeds and breaking the relationship between the mechanical stretching and triggering of the next contraction on the other side. This confirmed the ion channels were indeed involved with the rhythmic contractions.

"By leveraging cardiac mechano-electrical signaling between two layers of muscle, we recreated the cycle where each contraction results automatically as a response to the stretching on the opposite side," saysHarvard University bioengineer Keel Yong Lee.

"The results highlight the role of feedback mechanisms in muscular pumps such as the heart."

Parker and colleagues also integrated a pacemaker-like system into the biohybrid: an isolated cluster of cells that control the frequency and coordination of these movements.

"Because of the two internal pacing mechanisms, our fish can live longer, move faster, and swim more efficiently than previous work," explainsbiophysics researcherSung-Jin Park, the co-first author of the study.

The tissue wide contractions of the biohybrid fish are comparable to the zebrafish that the biohybrid is modeled after more efficiently propelling the little device around than mechanical robotic systems.

"Rather than using heart imaging as a blueprint, we are identifying the key biophysical principles that make the heart work, using them as design criteria, and replicating them in a system, a living, swimming fish, where it is much easier to see if we are successful," says Parker.

This research was published in Science.

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Scientists Made a 'Fish' From Human Cardiac Cells, And It ...

Cardiac Stem Cells Comments Off on Scientists Made a ‘Fish’ From Human Cardiac Cells, And It … | March 22nd, 2022

March 17, 2022 2:15 pm ET

First Phase 3 Study To Demonstrate Statistically Significant Improvement in DFS in the Adjuvant Setting for Patients With Stage IB-IIIA NSCLC Regardless of PD-L1 Expression

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, the European Organisation for Research and Treatment of Cancer (EORTC) and the European Thoracic Oncology Platform (ETOP) today announced results from the pivotal Phase 3 KEYNOTE-091 trial, also known as EORTC-1416-LCG/ETOP-8-15 PEARLS. The study found that adjuvant treatment with KEYTRUDA significantly improved disease-free survival (DFS), one of the dual primary endpoints, reducing the risk of disease recurrence or death by 24% compared to placebo (hazard ratio [HR]=0.76 [95% CI, 0.63-0.91]; p=0.0014) in patients with stage IB (4 centimeters) to IIIA non-small cell lung cancer (NSCLC) following surgical resection regardless of PD-L1 expression. Median DFS was 53.6 months for KEYTRUDA versus 42.0 months for placebo, an improvement of nearly one year. These data are being presented today during a European Society for Medical Oncology (ESMO) Virtual Plenary and will be shared with regulatory authorities worldwide.

These are the first positive results for KEYTRUDA in the adjuvant setting for non-small cell lung cancer, and represent the sixth positive pivotal study evaluating a KEYTRUDA-based regimen in earlier stages of cancer, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. KEYTRUDA has become foundational in the treatment of metastatic non-small cell lung cancer, and we are pleased to present these data showing the potential of KEYTRUDA to help more patients with lung cancer in earlier stages of disease. We thank the patients, their caregivers and investigators for participating in this study.

As previously announced, there was also an improvement in DFS for patients whose tumors express PD-L1 (tumor proportion score [TPS] 50%) treated with KEYTRUDA compared to placebo, the other dual primary endpoint; these results did not reach statistical significance per the pre-specified statistical plan (HR=0.82 [95% CI, 0.57-1.18]; p=0.14). Among these patients, median DFS was not reached in either arm. Additionally, a favorable trend in overall survival (OS), a key secondary endpoint, was observed for KEYTRUDA versus placebo regardless of PD-L1 expression (HR=0.87 [95% CI, 0.67-1.15]; p=0.17); these OS data are not mature and did not reach statistical significance at the time of this interim analysis. The trial will continue to evaluate DFS in patients whose tumors express high levels of PD-L1 (TPS 50%) and OS. The safety profile of KEYTRUDA in this study was consistent with that observed in previously reported studies.

Lung cancer is most treatable at earlier stages, and adding treatment after surgery may help reduce the risk of recurrence, said Professor Mary O'Brien, consultant medical oncologist and head of the Lung Unit at The Royal Marsden NHS Foundation Trust and professor of practice (medical oncology) at Imperial College London, as well as co-principal investigator. We are encouraged by these new Phase 3 data, as they represent the first time adjuvant immunotherapy has demonstrated a statistically significant and clinically meaningful improvement in disease-free survival for patients with stage IB-IIIA non-small cell lung cancer.

While significant advancements have been made in the treatment of metastatic non-small cell lung cancer, there remains an unmet need for patients with earlier stages of this disease, as up to 43% of them will experience disease recurrence following surgery, said Dr. Luis Paz-Ares, chair of the medical oncology department, Hospital Universitario Doce de Octubre, Madrid, Spain and co-principal investigator. The positive disease-free survival data observed in this study with the use of KEYTRUDA in the adjuvant setting has the potential to have important implications for how we treat patients with stage IB-IIIA non-small cell lung cancer.

In addition to KEYNOTE-091, five other pivotal trials evaluating a KEYTRUDA-based regimen in patients with earlier stages of cancer met their primary endpoint(s). These trials included: KEYNOTE-716 in stage IIB and IIC melanoma; KEYNOTE-054 in stage III melanoma; KEYNOTE-564 in renal cell carcinoma; KEYNOTE-522 in triple-negative breast cancer; and KEYNOTE-057 in Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer.

Merck has an extensive clinical development program in lung cancer and is advancing multiple registration-enabling studies, with research directed at earlier stages of disease and novel combinations. Key studies in earlier stages of NSCLC include KEYNOTE-091, KEYNOTE-671, KEYNOTE-867 and KEYLYNK-012.

Study Design and Additional Data From KEYNOTE-091

KEYNOTE-091, also known as EORTC-1416-LCG/ETOP-8-15 PEARLS, is a randomized, Phase 3 trial (ClinicalTrials.gov, NCT02504372) sponsored by Merck and conducted in collaboration with EORTC and ETOP evaluating KEYTRUDA compared to placebo for the adjuvant treatment of patients with stage IB (4 centimeters) to IIIA NSCLC following surgical resection (lobectomy or pneumonectomy) and with adjuvant chemotherapy when indicated. The dual primary endpoints are DFS in the overall population and in patients whose tumors express PD-L1 (TPS 50%). Disease-free survival is calculated as the time from randomization to the date of disease recurrence, occurrence of second primary lung cancer, occurrence of second malignancy, or death from any cause, whichever occurs first. The secondary endpoints include OS and lung cancer-specific survival (the time from randomization to date of death due to lung cancer specifically). The study randomized 1,177 patients (1:1) to receive either KEYTRUDA (200 mg intravenously [IV] every three weeks [Q3W] for one year or maximum 18 doses; n=590); or placebo (IV Q3W for one year or maximum 18 doses; n=587). The median number of doses was 17 for KEYTRUDA and 18 for placebo. As of data cut-off for this interim analysis (September 20, 2021), median time from randomization to data cut-off was 35.6 months (range, 16.5-68.0 months).

Grade 3 adverse events occurred in 34.1% of patients receiving KEYTRUDA and 25.8% of patients receiving placebo. Adverse events resulting in discontinuation of any treatment occurred in 19.8% of patients receiving KEYTRUDA and 5.9% of patients receiving placebo; there were four treatment-related deaths in the KEYTRUDA arm and no treatment-related deaths in the placebo arm.

About EORTC

The European Organisation for Research and Treatment of Cancer (EORTC) is a non-governmental, non-profit organisation, which unites clinical cancer research experts, throughout Europe, to define better treatments for cancer patients to prolong survival and improve quality of life. Spanning from translational to large, prospective, multi-centre, phase III clinical trials that evaluate new therapies and treatment strategies as well as patient quality of life, its activities are coordinated from EORTC Headquarters, a unique international clinical research infrastructure, based in Brussels, Belgium.

For further information, please visit the EORTC website: http://www.eortc.org.

About ETOP

The European Thoracic Oncology Platform (ETOP) is a foundation promoting exchange and research in the field of thoracic malignancies in Europe. It is a not-for-profit organization, domiciled in Bern, Switzerland. Since 2009 ETOP been able to bring together international leaders in field of thoracic malignancies from all disciplines and has continuously enlarged its clinical trial and translational research activity in collaboration with many groups and institutions from 20 countries from Europe and beyond.

For further information, please visit the ETOP website: http://www.etop-eu.org.

About Lung Cancer

Lung cancer is the leading cause of cancer death worldwide. In 2020 alone, there were more than 2.2 million new cases and 1.8 million deaths from lung cancer globally. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 82% of all cases. In the U.S., the overall five-year survival rate for patients diagnosed with lung cancer is 24%, a 14% improvement over the last five years. Improving survival rates are due in part to earlier detection and screening, reduction in smoking, advances in diagnostic and surgical procedures as well as the introduction of new therapies.

About Mercks Research in Lung Cancer

Merck is advancing research aimed at transforming the way lung cancer is treated, with a goal of improving outcomes for patients affected by this deadly disease. Through nearly 200 clinical trials evaluating more than 36,000 patients around the world, Merck is at the forefront of lung cancer research. In advanced NSCLC, KEYTRUDA has four approved U.S. indications (see indications below), and is approved in advanced NSCLC in more than 95 countries. Among Mercks research efforts are trials focused on evaluating KEYTRUDA in earlier stages of lung cancer as well as identifying new combinations and coformulations with KEYTRUDA.

About Mercks Early-Stage Cancer Clinical Program

Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (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 1,700 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 Indications for KEYTRUDA (pembrolizumab) in the U.S.

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:

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.

See additional selected indications for KEYTRUDA in the U.S. after the Selected Important Safety Information

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 PD-1 or the 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. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. 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

First-line treatment of advanced RCC in combination therapy with axitinib (KEYNOTE-426)

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) of patients. 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 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, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, 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%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054.

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those 1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each).

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or mUC. Serious adverse reactions occurred in 42% of patients; those 2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or mUC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those 2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those 2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of 5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%).

The most common adverse reactions (reported in 20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.

In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).

Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those 3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).

KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (1%) was colitis (1%).

For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%).

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

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Relatlimab is the third immune checkpoint inhibitor from Bristol Myers Squibb, adding to the Company's growing and differentiated oncology portfolio

Bristol Myers Squibb (NYSE: BMY) today announced that Opdualag TM (nivolumab and relatlimab-rmbw), a new, first-in-class, fixed-dose combination of nivolumab and relatlimab, administered as a single intravenous infusion, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. 1 The approval is based on the Phase 2/3 RELATIVITY-047 trial, which compared Opdualag (n=355) to nivolumab alone (n=359). 1,2

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20220304005561/en/

Opdualag Logo, Bristol Myers Squibb

The trial met its primary endpoint, progression-free survival (PFS), and Opdualag more than doubled the median PFS when compared to nivolumab monotherapy, 10.1 months (95% Confidence Interval [CI]: 6.4 to 15.7) versus 4.6 months (95% CI: 3.4 to 5.6); (Hazard Ratio [HR] 0.75; 95% CI: 0.62 to 0.92, P =0.0055). 1 The Opdualag safety profile was similar to that previously reported for nivolumab. 1,2 No new safety events were identified with the combination when compared to nivolumab monotherapy. 1,2 Grade 3/4 drug-related adverse events were 18.9% in the Opdualag arm compared to 9.7% in the nivolumab arm. 2 Drug-related adverse events leading to discontinuation were 14.6% in the Opdualag arm compared to 6.7% in the nivolumab arm. 2

"Since the approval of the first immune checkpoint inhibitor more than 10 years ago, we've seen immunotherapy, alone and in combination, revolutionize the treatment of patients with advanced melanoma," said F. Stephen Hodi, M.D., director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute. 3 "Today's approval is particularly significant, as it introduces an entirely new combination of two immunotherapies that may act together to help improve anti-tumor response by targeting two different immune checkpoints LAG-3 and PD-1." 1,2

Opdualag is associated with the following Warnings & Precautions: severe and fatal immune-mediated adverse reactions (IMARs) including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis and other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); and embryo-fetal toxicity. 1 Please see Important Safety Information below.

"While we have made great progress in the treatment of advanced melanoma over the past decade, we are committed to expanding dual immunotherapy treatment options for these patients," said Samit Hirawat, chief medical officer, global drug development, Bristol Myers Squibb. 3 "Inhibiting LAG-3 with relatlimab, in a fixed-dose combination with nivolumab, represents a new treatment approach that builds on our legacy of bringing innovative immunotherapy options to patients. The approval of a new medicine that includes our third distinct checkpoint inhibitor marks an important step forward in giving patients more options beyond monotherapy treatment."

Lymphocyte activation gene-3 (LAG-3) and programmed death-1 (PD-1) are two distinct inhibitory immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes, thus contributing to tumor-mediated T-cell exhaustion. 2 The combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cell activation compared to the activity of either antibody alone. 1 Relatlimab (in combination with nivolumab) is the first LAG-3-blocking antibody to demonstrate a benefit in a Phase 3 study. 1 It is the third checkpoint inhibitor (along with anti-PD-1 and anti-CTLA-4) for Bristol Myers Squibb.

"Today's approval is exciting news and offers new hope to the melanoma community. The availability of this treatment combination may enable patients to potentially benefit from a new, first-in-class dual immunotherapy," said Michael Kaplan, president and CEO, Melanoma Research Alliance.

The FDA-approved dosing for adult patients and pediatric patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered intravenously every four weeks. 1 The recommended dosage for pediatric patients 12 years of age or older who weigh less than 40 kg, and pediatric patients younger than 12 years of age, has not been established. 1

This application was approved under the FDA's Real-Time Oncology Review (RTOR) pilot program, which aims to ensure that safe and effective treatments are available to patients as early as possible. 4 The review was also conducted under the FDA's Project Orbis initiative, which enabled concurrent review by the health authorities in Australia, Brazil and Switzerland, where the application remains under review.

About RELATIVITY-047

RELATIVITY-047 is a global, randomized, double-blind Phase 2/3 study evaluating the fixed-dose combination of nivolumab and relatlimab versus nivolumab alone in patients with previously untreated metastatic or unresectable melanoma. 1,2 The trial excluded patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high dose corticosteroids or immunosuppressive medications, uveal melanoma, and active or untreated brain or leptomeningeal metastases. 1 The primary endpoint of the trial is progression-free survival (PFS) determined by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). 1 The secondary endpoints are overall survival (OS) and objective response rate (ORR). 1 A total of 714 patients were randomized 1:1 to receive a fixed-dose combination of nivolumab (480 mg) and relatlimab (160 mg) or nivolumab (480 mg) by intravenous infusion every four weeks until disease progression or unacceptable toxicity. 1

Select Safety Profile From RELATIVITY-047

Adverse reactions leading to permanent discontinuation of Opdualag occurred in 18% of patients. 1 Opdualag was interrupted due to an adverse reaction in 43% of patients. 1 Serious adverse reactions occurred in 36% of patients treated with Opdualag. 1 The most frequent (1%) serious adverse reactions were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%). 1 Fatal adverse reactions occurred in three (0.8%) patients treated with Opdualag and included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. 1 The most common (20%) adverse reactions were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%). 1 The Opdualag safety profile was similar to that previously reported for nivolumab. 1,2 No new safety events were identified with the combination when compared to nivolumab monotherapy. 1,2 Grade 3/4 drug-related adverse events were 18.9% in the Opdualag arm compared to 9.7% in the nivolumab arm. 2 Drug-related adverse events leading to discontinuation were 14.6% in the Opdualag arm compared to 6.7% in the nivolumab arm. 2

About Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. 5 Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs. 5,6 The incidence of melanoma has been increasing steadily for the last 30 years. 5,6 In the United States, approximately 99,780 new diagnoses of melanoma and about 7,650 related deaths are estimated for 2022. 5 Melanoma can be mostly treatable when caught in its very early stages; however, survival rates can decrease as the disease progresses. 6

OPDUALAG INDICATION

Opdualag TM (nivolumab and relatlimab-rmbw) is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

OPDUALAG IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions (IMARs) listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

IMARs which may be severe or fatal, can occur in any organ system or tissue. IMARs can occur at any time after starting treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While IMARs usually manifest during treatment, they can also occur after discontinuation of Opdualag. Early identification and management of IMARs are essential to ensure safe use. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying IMARs. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected IMARs, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if Opdualag 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 IMARs are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

Opdualag can cause immune-mediated pneumonitis, which may be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.7% (13/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 1.4% of patients.

Immune-Mediated Colitis

Opdualag can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was 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 diarrhea or colitis occurred in 7% (24/355) of patients receiving Opdualag, including Grade 3 (1.1%) and Grade 2 (4.5%) adverse reactions. Colitis led to permanent discontinuation of Opdualag in 2% and withholding of Opdualag in 2.8% of patients.

Immune-Mediated Hepatitis

Opdualag can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Immune-mediated hepatitis occurred in 6% (20/355) of patients receiving Opdualag, including Grade 4 (0.6%), Grade 3 (3.4%), and Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent discontinuation of Opdualag in 1.7% and withholding of Opdualag in 2.3% of patients.

Immune-Mediated Endocrinopathies

Opdualag can cause primary or secondary adrenal insufficiency, hypophysitis, thyroid disorders, and Type 1 diabetes mellitus, which can be present with diabetic ketoacidosis. Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. In patients receiving Opdualag, adrenal insufficiency occurred in 4.2% (15/355) of patients receiving Opdualag, including Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdualag in 1.1% and withholding of Opdualag in 0.8% of patients.

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 clinically indicated. Hypophysitis occurred in 2.5% (9/355) of patients receiving Opdualag, including Grade 3 (0.3%) and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 0.6% of patients.

Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Thyroiditis occurred in 2.8% (10/355) of patients receiving Opdualag, including Grade 2 (1.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of Opdualag. Thyroiditis led to withholding of Opdualag in 0.3% of patients. Hyperthyroidism occurred in 6% (22/355) of patients receiving Opdualag, including Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of Opdualag. Hyperthyroidism led to withholding of Opdualag in 0.3% of patients. Hypothyroidism occurred in 17% (59/355) of patients receiving Opdualag, including Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 2.5% of patients.

Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated. Diabetes occurred in 0.3% (1/355) of patients receiving Opdualag, a Grade 3 (0.3%) adverse reaction, and no cases of diabetic ketoacidosis. Diabetes did not lead to the permanent discontinuation or withholding of Opdualag in any patient.

Immune-Mediated Nephritis with Renal Dysfunction

Opdualag can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear etiology. In patients receiving Opdualag, immune-mediated nephritis and renal dysfunction occurred in 2% (7/355) of patients, including Grade 3 (1.1%) and Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 0.6% of patients.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-Mediated Dermatologic Adverse Reactions

Opdualag can cause immune-mediated rash or dermatitis, defined as requiring use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Rash with eosinophilia and systemic symptoms has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-mediated rash occurred in 9% (33/355) of patients, including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions. Immune-mediated rash did not lead to permanent discontinuation of Opdualag. Immune-mediated rash led to withholding of Opdualag in 1.4% of patients.

Immune-Mediated Myocarditis

Opdualag can cause immune-mediated myocarditis, which is defined as requiring use of steroids and no clear alternate etiology. The diagnosis of immune-mediated myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly arrange cardiology consultation with diagnostic workup. If clinically confirmed, permanently discontinue Opdualag for Grade 2-4 myocarditis.

Myocarditis occurred in 1.7% (6/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse reactions. Myocarditis led to permanent discontinuation of Opdualag in 1.7% of patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant IMARs occurred at an incidence of ardiac/Vascular: 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 IMARs, consider a Vogt-Koyanagi-Haradalike syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica; Endocrine: hypoparathyroidism; Other (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

Opdualag can cause severe infusion-related reactions. Discontinue Opdualag in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild to moderate infusion-related reactions. In patients who received Opdualag as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, 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 PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, Opdualag can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Opdualag for at least 5 months after the last dose of Opdualag.

Lactation

There are no data on the presence of Opdualag in human milk, the effects on the breastfed child, or the effect on milk production. Because nivolumab and relatlimab may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with Opdualag and for at least 5 months after the last dose.

Serious Adverse Reactions

In Relativity-047, fatal adverse reaction occurred in 3 (0.8%) patients who were treated with Opdualag; these included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. Serious adverse reactions occurred in 36% of patients treated with Opdualag. The most frequent serious adverse reactions reported in 1% of patients treated with Opdualag were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%).

Common Adverse Reactions and Laboratory Abnormalities

The most common adverse reactions reported in 20% of the patients treated with Opdualag were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).

The most common laboratory abnormalities that occurred in 20% of patients treated with Opdualag were decreased hemoglobin (37%), decreased lymphocytes (32%), increased AST (30%), increased ALT (26%), and decreased sodium (24%).

Please see U.S. Full Prescribing Information for Opdualag .

OPDIVO + YERVOY INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

OPDIVO + YERVOY IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. 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 OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, 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 immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (

In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) 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. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%).

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. 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 clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; 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, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR 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-Haradalike syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

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Bristol Myers Squibb to Demonstrate the Strength of its Growing Cardiovascular Portfolio at the American College of Cardiology's 71st Annual...

Cardiac Stem Cells Comments Off on Bristol Myers Squibb to Demonstrate the Strength of its Growing Cardiovascular Portfolio at the American College of Cardiology’s 71st Annual… | March 22nd, 2022

According to the latest report by IMARC Group, titled Stem Cell Banking Market: Global Industry Trends, Share, Size, Growth, Opportunity and Forecast 2021-2026 the global market reached a value of US$ 10.4 Billion in 2020. Stem cell banking refers to the process of collecting, storing and freezing stem cells for potential future use. Embryo, placenta, umbilical cord, bone marrow and cord blood are some of the common sources for obtaining stem cells. These cells are cryopreserved and are used to replace damaged organs, tissues and treat various diseases, such as leukemia, diabetes, thalassemia and cardiac disorders. Moreover, stem cells can regenerate and produce red blood cells (RBCs), platelets and white blood cells to protect the body in case of an infection. As a result, they are widely used for clinical, personalized and research applications.

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The global stem cell banking market is primarily being driven by the rising geriatric population. Due to the increasing prevalence of fatal chronic diseases, preserved stem cells are used in various medical therapies for the treatment of immune, blood, degenerative and metabolic disorders. Moreover, various technological advancements, such as the utilization of artificial intelligence (AI) solutions to identify productive and healthy stem cells, are providing a thrust to the market growth. Other factors, including the implementation of various government initiatives promoting public health, along with significant improvements in the medical infrastructure, are creating a positive outlook for the market. Looking forward, IMARC Group expects the market to reach a value of US$ 21.5Billion by 2026.

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As the novel coronavirus (COVID-19) crisis takes over the world, we are continuously tracking the changes in the markets, as well as the industry behaviors of the consumers globally and our estimates about the latest market trends and forecasts are being done after considering the impact of this pandemic.

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Stem Cell Banking Market: Top Companies, Investment Trend, Growth & Innovation Trends 2021-2026 The Bite - The Bite

Cardiac Stem Cells Comments Off on Stem Cell Banking Market: Top Companies, Investment Trend, Growth & Innovation Trends 2021-2026 The Bite – The Bite | March 22nd, 2022

One of the most important sacrifices a person can make is to offer the gift of life to another. Especially if they dont know whos receiving the gift, and they have to give up something they may need like the marrow in their bones.

Donating bone marrow to someone who is in distress, and may die without a transplant, is a selfless act. Blood diseases, such as leukemia, are horrific, causing tiredness, infections, and pain. A bone marrow transplant replaces damaged or diseased blood forming cells, also called stem cells, with healthy stem cells.

Those in need of a bone marrow transplant are put on a waiting list, because they need to be matched by a donor. Fortunately, there is a registry for those willing to donate their bone marrow.

Caitlin Stone-Webber of Port Austin was willing. She registered to be a donor while in college.

Back in 2011, I was a student at Central Michigan University, Stone-Webber said. There was a student who had a form of leukemia. They were doing a bone marrow drive, testing anyone who was willing to go on the registry, to see if there was a match on campus.

She was not compatible, but her name remained on the registry.

Its an international registry, Stone-Webber said. There are a lot of different groups that help build up this registry.

Five years ago, Stone-Webber received word she had matched. She went through a process of confirmation. Something happened on the recipients end, so the process wasnt completed. Two years later, the same thing happened. Earlier this year, she was contacted again. This time, the donation went through.

Upon receipt of the notification that shed matched, Stone-Webber was required to undergo a physical. The donation process is tiring, and the donor needs to be in good health.

The physical included checking her veins.

Even though its bone marrow, it no longer has to be hip surgery, Stone-Webber said. They can do whats called peripheral cell donation.

Peripheral blood stem celldonation is a method of collecting blood-forming cells for the transplant. The same blood-forming cells that are found in bone marrow are also found in the circulating (peripheral) blood. It is a procedure called apheresis.

They take your blood from one arm, Stone-Webber said. It goes through a machine, takes out your stem cells, and goes back in your other arm.

In addition to the physical, she also had to have injections that raised her stem cell count.

You do four days of injections, Stone-Webber said. And then the day of the procedure, you receive injections, as well.

The injections leading up to the procedure were given at her home.

Because of my size, I actually had to have two shots each day, one in each arm, Stone-Webber said. The nurse would come in, take my vitals, give the shots and then wait to make sure there was no reaction.

Although some people work throughout this stage, Stone-Webber took time off.

So I was able to just go to bed, she said. I was very tired, and my bones hurt. Thats where your bodys creating these extra stem cells ... in your bones. I was very aware of where every bone in my body was, but not at the same time. The first day it was in my legs. They hurt. The second day it was in my hips. One day it was in my toes. It was the strangest thing.

It was a normal part of the process.

They say to prepare for that, that your bones are going to hurt, Stone-Webber said.

She was told to take Tylenol for pain, as well as, oddly enough, Claritin, which relieves allergies.

They said they dont really know what part of the (Claritin) makes it work, but it works, Stone-Webber said.

The procedure took place at a hospital, although Stone-Webber isnt allowed to say where.

When you donate to someone, you stay anonymous until a year from the donation date, she said. I had to sign a confidentially document saying I could talk about the procedure I can talk about my experience. But I cant talk about where I donated.

Details on the identity of the recipient are unknown to her.

I know gender, Stone-Webber said. I know age. I know country. And, I know the type of leukemia. I didnt know what country they were in until post donation. Thats something I thought was real cool about being able to donate right now, is that with the world the way it is, to be able to help someone without knowing their political affiliation, or religion. None of that mattered. I was just helping another person.

Due to the fact that the bone marrow registry is international there are also national registries potential donors should be aware they may have to travel if they match. Stone-Webbers expenses, including travel, food, and lodging, were covered by the nonprofit organization the donation was set up through.

I was never billed for anything, Stone-Webber said.

All it cost her was time and a little discomfort.

The way I looked at it is, anyone can be sick for four or five days in order to save someones life, Stone-Webber said.

The actual donation took place in the course of one day. She was hooked up to a machine that recycled her blood. Due to her size her veins werent large enough for the procedure Stone-Webber required a catheter to be inserted in her jugular vein.

I could feel the catheter when I swallowed, she said. And when they pulled it out, I could feel a little bit of discomfort. For a couple days afterward, there were times I was a little uncomfortable.

Once the procedure started, Stone-Webber was confined to a hospital bed. She was given medication that allowed her to remain still, so the machine could recycle her blood.

It went in and out the same port, she said. I was hooked up to the machine for five hours, and it cycled my blood through the machine four and a half times. It was kind of cool to think someone has invented this machine that can cycle blood. Because of the injections, my body was still making stem cells, so that machine could continue to get out everything this recipient could need.

A bone marrow transplant is beneficial to those receiving the new stem cells. In some cases it may even provide a cure for their disease.

Its mostly for blood-related cancers, Stone-Webber said. There may be other blood-related disorders and diseases that it could help with. In some cases the donation is a treatment to kind of stall things. In others, its a cure. I was told the day of the donation, that my donation would be a cure that when the patient received my donated stem cells, it would cure their leukemia providing its a successful donation and their body accepts it.

The bone marrow registry can be accessed through a number of nonprofit organizations, including http://www.dkms.org and http://www.bethematch.org, which Stone-Webber worked with.

As of now, she knows her stem cells have been received by the recipient, but has no idea of the outcome. At the end of the year required by her confidentiality agreement, she would like to know whether or not they were affective. After all, her stem cells are now in someone else.

I think we now connect in a different way than most people would, Stone-Webber said. I think I would like the opportunity to know how theyre doing.

That connection is a bone marrow transplant, the gift of life. Stone-Webber would do it again.

For further information on bone marrow transplants and the bone marrow registry, email Stone-Webber at caitlinstone22@gmail.com or visit http://www.dkms.org or http://www.bethematch.org.

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Port Austin woman gives gift of life with marrow donation - Huron Daily Tribune

Bone Marrow Stem Cells Comments Off on Port Austin woman gives gift of life with marrow donation – Huron Daily Tribune | March 22nd, 2022

An article published in the journal Biomaterials shows that [emailprotected]2 nanoparticles (NPs) synthesized with a short bacteriophage-selected mesenchymal stem cell(MSC) targeting peptide allowed the MSCs to take up these NPs. NP-modified MSCs produced greatly improved therapy of Rheumatoid Arthritis(RA) using stem cells.

Study:Highly effective rheumatoid arthritis therapy by peptide-promoted nanomodification of mesenchymal stem cells. Image Credit:Emily frost/Shutterstock.com

RA, which is marked by progressive joint degeneration andsynovial inflammation, is one ofthe primary widespread inflammatory arthritis thataffectsaround 1 % of the global population, however, it currently lacks an effective treatment.

Glucocorticoids (GCs), disease-modifying anti-rheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs)are the three maintypes of medicationscurrently used in clinical practice.

GCs and NSAIDscan help with joint pain and stiffness, but they may cause side effects such asheart problems, osteoporosis, infections andgastric ulcers.

Standard DMARDs, like methotrexate (MTX), can lessen swelling by inhibiting the synthesis of pro-inflammatory cytokines and have little effect on cartilage degeneration. MTX, on the other hand, has a short plasma half-lifeand a poor concentration of the drug in the inflammatory region of the body.

Other side effects may also include liver and kidney damage, bone marrow depletion, and gastrointestinal problems. Biological DMARDs have been rapidly developed in recent years, thoughtheir action slows the progression of structural damage by reducing inflammation and have issues including drug resistance and the potential to cause significant infections and malignant tumors.

Multilineage differentiation, inflammatory site and immunomodulationhoming are all features of MSCs. These distinctivecharacteristicsallowMSCs to become apotential treatmentfora variety ofinflammatory and degenerativediseases, including the treatment of RA,through cell therapy. Unfortunately, over 50 % of patients do not react to MSC treatment, and the therapeutic benefit of MSCs is only temporary.

Firstly, MSCs are susceptible to the inflammatory milieu and so lose their functions of immune-regulationwhen disclosed in an inflamed joint. Reactive oxygen species (ROS) are thought to be engaged in the inflammation development of RA and hence damaging to MSCs, as seen by the gradualdecline in the quantity of MSCs in RA patients' synovial fluid.

Secondly, while the direct impacts of MSCs on tissue regeneration in RA are unknown, an evidentclinical experiment found that MSC injections increased hyaline cartilage regeneration in RA patients. Nevertheless, the unregulated distinction of MSCs can alsoresult in the development of tumors andthe inability of cartilage repair.

As a result, it is important for an optimal stem cell strategy to include MSCs that have the ability to preserve their bio functions and chondrogenically develop to regenerate cartilage under the oxidative stress caused by RA.

According to thisstudy, RA therapy could be enhanced byshort targeting peptide-promoted nanomodification of MSCs. To begin with, [emailprotected]2 NPs wereproduced due to some of theirelements' appealing features. Mn and Cu both are critical trace components in the human body, and they play a keyrole in the production of natural Mnsuperoxide dismutase (SOD) and Cu-ZnSOD, respectively.

Cu and Mn can also encourage stem cell chondrogenesis. The study further explains the modification of [emailprotected]2 NPs with MSC-targeting peptides to increase the passage of the nanoparticles into MSCs since transporting nanomaterials into modifications of MSCs is still a difficult task.

To make [emailprotected]2/MET NPs, [emailprotected]2 NPs were injected with metformin. Lastly, MSCs were allowedto take up these NPs and utilizethem to effectively limit synovial inflammation and maintain cartilage structure, alleviating arthritic symptoms greatly.

This study demonstrates that VCMM-MCSs werecreated by engineering MSCs with catalase (CAT) and superoxide dismutase (SOD)- like activity using dynamically MSC-targeting [emailprotected]2/MET NPs.

The biological features of these cells required in stem cell treatment, such as chondrogenesis, anti-inflammation, cell migration, and increased survival under oxidative stress, were improved by VCMM-MCSs.

Consequently, the VCMM-MSCs injections reduced cartilage damage andsynovial hyperplasiain adjuvant-induced arthritis (AIA) as well as collagen-induced arthritis (CIA) models, substantially reducing arthritic symptoms. Since oxidative stress is present in numerous degenerative and inflammatory disorders, this strategy of altering MSCs with NPs could be applied to treat a number of other disorders as well as to achieve faster tissue healing using stem cell therapy.

Lu, Y., Li, Z. et al. (2022). Highly effective rheumatoid arthritis therapy by peptide-promoted nanomodification of mesenchymal stem cells. Biomaterials. Available at: https://www.sciencedirect.com/science/article/pii/S0142961222001132?via%3Dihub

Disclaimer: The views expressed here are those of the author expressed in their private capacity and do not necessarily represent the views of AZoM.com Limited T/A AZoNetwork the owner and operator of this website. This disclaimer forms part of the Terms and conditions of use of this website.

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Nano-Improvements to Rheumatoid Arthritis Stem Cell Therapy Show Success - AZoNano

Bone Marrow Stem Cells Comments Off on Nano-Improvements to Rheumatoid Arthritis Stem Cell Therapy Show Success – AZoNano | March 22nd, 2022

REDWOOD CITY, Calif., March 21, 2022 (GLOBE NEWSWIRE) --Jasper Therapeutics, Inc. (NASDAQ: JSPR), a biotechnology company focused on hematopoietic cell transplant therapies, today announced changes to its management team, including the promotions of Jeet Mahal to the newly created position of Chief Operating Officer, and of Wendy Pang, M.D., Ph.D., to Senior Vice President of Research and Translational Medicine. Both promotions are effective as of March 21, 2022. Jasper also announced that a new position of Chief Medical Officer has been created, for which an active search is underway. Judith Shizuru, M.D. PhD, co-founder, and Scientific Advisory Board Chairwoman will lead clinical development activities on an interim basis and Kevin Heller, M.D., EVP of Research and Development, will be transitioning to a consultant role.

Based on the recent progress with JSP191, our anti-CD117 monoclonal antibody, as a targeted non-toxic conditioning agent and our mRNA hematopoietic stem cell program we have decided to advance Jaspers organizational structure with the creation of the roles of Chief Operating Officer and Chief Medical Officer and by elevating our research and translational medicine team to report directly to the CEO, said Ronald Martell, CEO of Jasper Therapeutics. We also are pleased that Dr. Shizuru will lead clinical development activities on an interim basis, a role she served during the companys founding in 2019.

These changes will allow us to advance our upcoming pivotal trial of JSP191 in AML/ MDS and execute on our pipeline opportunities with a best-in-class organization, continued Mr. Martell. We also wish to thank Dr. Heller for his help advancing JSP191 through our initial AML/MDS transplant study.

In the two plus years since we founded Jasper and received our initial funding, the company has been able to advance JSP191 in two clinical studies, develop our mRNA stem cell graft platform and publicly list on NASDAQ, said Dr. Shizuru, co-founder and member of the Board of Directors of Jasper Therapeutics. These changes will strengthen the companys ability to advance the field of hematopoietic stem cell therapies and bring cures to patients with hematologic cancers, autoimmune diseases and debilitating genetic diseases."

Mr. Mahal joined Jasper in 2019 as Chief Finance and Business Officer and has led Finance, Business Development, Marketing and Facilities/ IT since the companys inception. Prior to joining Jasper, he was Vice President, Business Development and Vice President, Strategic Marketing at Portola Pharmaceuticals, where he led the successful execution of multiple business development partnerships for Andexxa, Bevyxxaand cerdulatinib. He also played a key role in the companys equity financings, including its initial public offering and multiple royalty transactions. Earlier in his career, Mr. Mahal was Director, Business and New Product Development, at Johnson & Johnson on the Xareltodevelopment and strategic marketing team. Mr. Mahal holds a BA in Molecular and Cell Biology from U.C. Berkeley, a Masters in Molecular and Cell Biology from the Illinois Institute of Technology, a Masters in Engineering from North Carolina State University and an MBA from Duke University.

Dr. Pang joined Jasper in 2020 and has led early research and development including leading creation of the companys mRNA stem cell graft platform and playing a pivotal role in advancing JSP191 across multiple clinical studies. Previously Dr. Pang was an Instructor in the Division of Blood and Marrow Transplantation at Stanford University and the lead scientist in the preclinical drug development of an anti-CD117 antibody program. She was the lead author on the proof-of-concept studies showing that an anti-CD117 antibody therapy targets disease-initiating human hematopoietic (blood cell-forming) stem cells in myelodysplastic syndrome (MDS). She has authored numerous publications on the characterization of hematopoietic stem and progenitor cell behavior in hematopoieticdiseases, as well as hematopoietic malignancies, including MDS and acute myeloid leukemia (AML), and in hematopoietic stem cell transplantation. Dr. Pang earned her AB and BM in Biology from Harvard University and her MD and PhD in cancer biology from Stanford University.

Dr. Shizuru is a Professor of Medicine (Blood and Marrow Transplantation) and Pediatrics (Stem Cell Transplantation) at StanfordUniversity.She is the clinician-scientist co-founder of Jasper Therapeutics. Dr. Shizuru is an internationally recognized expert on the basic biology of blood stem cell transplantation and the translation of this biology to clinical protocols.Dr Shizuruis a member of the Stanford Blood and Marrow Transplantation (BMT) faculty, the Stanford Immunology Program, and the Institute for Stem Cell Biology and Regenerative Medicine. Shehas been an attending clinicianattendedon the BMT clinical service since 1997.Currently, she oversees a research laboratory focused on understanding the cellular and molecular basis of resistance to engraftment of transplantedallogeneic bone marrow blood stemcells and the way in which bone marrow grafts modify immune responses.Dr. Shizuru earned her BA from Bennington College and her MD and PhD in immunology from Stanford University

About Jasper Therapeutics

Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The company is advancing two potentially groundbreaking programs. JSP191, an anti-CD117 monoclonal antibody, is in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplantation. It is designed to enable safer and more effective curative allogeneic hematopoietic cell transplants and gene therapies. Jasper is also advancing JSP191 as a potential therapeutic for patients with lower risk Myelodysplastic Syndrome (MDS). Jasper Therapeutics is also advancing its preclinical mRNA hematopoietic stem cell graft platform, which is designed to overcome key limitations of allogeneic and autologous gene-edited stem cell grafts. Both innovative programs have the potential to transform the field and expand hematopoietic stem cell therapy cures to a greater number of patients with life-threatening cancers, genetic diseases and autoimmune diseases than is possible today. For more information, please visit us at jaspertherapeutics.com.

Forward-Looking Statements

Certain statements included in this press release that are not historical facts are forward-looking statements for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements are sometimes accompanied by words such as believe, may, will, estimate, continue, anticipate, intend, expect, should, would,plan,predict,potential,seem,seek,future,outlookandsimilarexpressionsthat predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements include, but are not limited to, statements regarding the potentialof the Companys JSP191 and mRNA engineered stem cell graft programs. Thesestatementsarebasedonvariousassumptions,whetherornotidentifiedinthispressrelease, and on the current expectations of Jasper and are not predictions of actual performance. These forward-lookingstatementsareprovidedforillustrativepurposesonlyandarenotintendedtoserve as, and must not be relied on by an investor as, a guarantee, an assurance, a prediction or a definitivestatementoffactorprobability.Actualeventsandcircumstancesaredifficultorimpossible to predict and will differ from assumptions. Many actual events and circumstances are beyond the control of Jasper. These forward-looking statements are subject to a number of risks and uncertainties, including general economic, political and business conditions; the risk that the potential product candidates that Jasper develops may not progress through clinical development or receive required regulatory approvals within expected timelines or at all; risks relating to uncertainty regarding the regulatory pathway for Jaspers product candidates; the risk that prior study results may not be replicated; the risk that clinical trials may not confirm any safety, potency or other product characteristics described or assumed in this press release; the risk that Jasper will be unable to successfully market or gain market acceptance of its product candidates; the risk that Jaspers product candidates may not be beneficialtopatientsorsuccessfullycommercialized;patientswillingnesstotrynewtherapiesand the willingness of physicians to prescribe these therapies; the effects of competition on Jaspers business; the risk that third parties on which Jasper depends for laboratory, clinical development, manufacturing and other critical services will fail to perform satisfactorily; the risk thatJaspers business, operations, clinical development plans and timelines, and supply chain could be adversely affected by the effects of health epidemics, including the ongoing COVID-19 pandemic; the risk that Jasper will be unable to obtain and maintain sufficient intellectual property protection foritsinvestigationalproductsorwillinfringetheintellectualpropertyprotectionofothers;andother risks and uncertainties indicated from time to time in Jaspers filings with the SEC. If any of these risksmaterializeorJaspersassumptionsproveincorrect,actualresultscoulddiffermateriallyfrom the results implied by these forward-looking statements. While Jasper may elect to update these forward-lookingstatementsatsomepointinthefuture,Jasperspecificallydisclaimsanyobligation to do so. These forward-looking statements should not be relied upon as representing Jaspers assessmentsofanydatesubsequenttothedateofthispressrelease.Accordingly,unduereliance should not be placed upon the forward-lookingstatements.

Contacts:

John Mullaly (investors)LifeSci Advisors617-429-3548jmullaly@lifesciadvisors.com

Jeet Mahal (investors)Jasper Therapeutics650-549-1403jmahal@jaspertherapeutics.com

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Jasper Therapeutics Announces Management Changes to Strengthen Leadership Team - BioSpace

Bone Marrow Stem Cells Comments Off on Jasper Therapeutics Announces Management Changes to Strengthen Leadership Team – BioSpace | March 22nd, 2022

London-based leukaemia patient Yvette Chin, 41, has just months to live unless a stem cell donor is found. PROVIDED TOCHINA DAILY

The family of a Chinese leukaemia patient in the United Kingdom has launched an urgent appeal calling for the East Asian community around the world to become stem cell donors.

Yvette Chin, 41, from London has acute lymphoblastic leukaemia, a rare aggressive blood cancer, and has just months to live unless a donor can be found.

Her brother, Colin Chin, 48, and sister-in-law Serena Chin are urging more people in the Chinese and East Asian community to register as stem cell donors to increase the chances of saving her life.

According to charity Anthony Nolan, which works in the areas of leukaemia and hematopoietic stem cell transplantation, 75 percent of UK patients will not find a matching donor in their families.

Only 72 percent of patients from white Caucasian backgrounds can find the best possible match from a stranger. This drops to 37 percent for patients from a minority ethnic background.

Yvette, who was diagnosed with the disease in May 2021, needs to have a stem cell transplant with a 90 percent genetic match.

The family hopes more people in the East Asian community in the UK and internationally can sign up to a bone marrow register to help Yvette and others in a similar position.

"Our family has registered but it's not enough. I hope if more people from the community know how quick and easy it is to do, and that it's literally lifesaving, we can find a match," Colin said.

"Not just for Yvette, but also for others who don't have time to wait. I'm asking for everyone to sign up and share #SwabForYvette on social media to spread awareness that we all have the power to save lives with a simple mouth swab."

Yvette's sister-in-law Serena hopes their campaign will help more people in ethnic minority groups gain a better understanding of what being a stem cell donor involves.

"When we looked into it, we realize Yvette isn't the only one in the community who needed this and that others are waiting for a donor, waiting for that second chance of life," she said. "Of course, we hope we find a match for Yvette, but I hope also we help save other people's lives as well who are in the same situation."

Yvette, a keen explorer who has scaled Mount Kilimanjaro, has been in and out of hospital for chemotherapy since her diagnosis last year. She took part in an experimental trial but in February she was told the trial had failed.

"After the trial, the leukaemia came back with so much ferocity and we still don't have a match, my brother wasn't a match and that was the reality that it was going to be difficult," Yvette said. "It feels like the stars have to align so much with me being in remission and finding a match."

Reshna Radiven, head of communications and engagement at DKMS UK, an international nonprofit bone marrow donor center, said ethnic minority communities are massively under-represented, especially the Chinese, Pakistani, Bangladeshi, Black-African and Black-Caribbean communities.

"There is an element of hesitancy, for some of the communities we know they don't trust the health system or the system generally in the countries that they're resident in," Radiven said. "But there is also a fundamental lack of awareness of the need for stem cell donors and the impact a stem cell donation can have for a cancer patient."

She added more work needs to be done to communicate and encourage people to become donors.

"You're very likely to find a match from a donor who is from the same ethnic community as you, so it's really important for all people to be represented in the register," Radiven said. "We offer the family and the patient hope, which is really significant when you're in a very difficult situation.

"In a world where we're trying to bridge the gap of inequality, we just want to get the word out there to encourage more bone marrow donations and blood too," Yvette said.

"I feel like the East Asian community has trepidation about doing that, so if they don't do it for me, then do it for someone else and bridge that stark statistic between our white Caucasian counterparts and everybody else."

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Family calls on East Asians to help by donating much-needed stem cells - China Daily

Bone Marrow Stem Cells Comments Off on Family calls on East Asians to help by donating much-needed stem cells – China Daily | March 22nd, 2022

Mixed-phenotype acute leukemia (MPAL) is a rare type of blood cancer. Typically, a doctor can classify the cancer as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), depending on the cells involved. However, MPAL presents with features of both AML and ALL.

Leukemia describes a cancer of the blood or bone marrow. There are many types of leukemia, and doctors typically classify them as either acute (sudden) or chronic (slow), depending on how quickly the cancer develops. They can then further classify these cancers depending on whether they affect myeloid or lymphocytic blood cells.

MPAL refers to a rare subtype of leukemia that displays no clear sign of origin and presents with features of both AML and ALL.

In this article, we will discuss MPAL leukemia, including the symptoms, diagnosis, treatment options, and outlook.

Mixed-phenotype acute leukemia (MPAL) is a rare type of acute leukemia where leukemia cells present with both myeloid and lymphocytic features. Some may also refer to this type of leukemia as acute leukemia of ambiguous lineage (ALAL), mixed-lineage leukemia, and acute undifferentiated leukemia.

In 2008, the World Health Organization (WHO) introduced the term MPAL to classify this group of blood cancers. Previously, the scientific community used other terms such as biphenotype acute leukemia to label these diseases.

A doctor may also further classify MPAL into bilineal or biphenotypic leukemia. The former refers to two separate populations of cells with myeloid and lymphoid origin, while the latter describes a single population of leukemia cells that express markers of both lymphoid and myeloid origin.

Some evidence suggests that the frequency of MPAL is 3%, while other research indicates that it accounts for roughly 25% of all acute leukemia diagnoses. MPAL can affect both children and adults.

As with other types of acute leukemia, the exact cause of MPAL is currently unknown. Some evidence suggests that MPAL may derive from alterations in blood stem cells that have the ability to undergo myeloid and lymphoid differentiation.

Research indicates that genetic alterations are associated with acute leukemias and may explain the abnormal development and maturation of white blood cells.

Certain genomic alterations may drive the biphenotypic expression in leukemia cells. Chromosome alterations that are often present in individuals with MPAL include Philadelphia chromosome and chromosome 11q23 abnormalities.

Potential risk factors for developing leukemia may include:

The symptoms of MPAL can occur suddenly and typically relate to problems with bone marrow. Symptoms can include:

Many of these symptoms are common to other conditions, including other types of leukemia. However, healthcare practitioners are aware of symptoms that may indicate MPAL leukemia and will request further testing if they think it is necessary.

Initially, doctors will likely use the same tools for diagnosing other forms of leukemia. These may include:

Due to the lack of consensus on the diagnostic criteria for MPAL, it can be difficult to diagnose the condition. The WHO diagnostic criteria provide a small list of specific lineage markers that can help diagnose MPAL.

Health experts use an immunophenotyping method, known as flow cytometry, on blood or bone marrow samples to identify these markers on leukemia cells.

This technique uses light to detect and measure the characteristics of cells. For an MPAL diagnosis, the sample will contain markers of both myeloid and lymphoid origin. This can also help guide if an AML or ALL treatment regimen will be more appropriate for a treatment plan.

If a doctor suspects an MPAL diagnosis, they will likely request genetic testing to identify the presence of genetic alterations, such as Philadelphia chromosome and chromosome 11q23 abnormalities. This is because a person with these alterations may require a more intensive treatment plan.

Treatment options for MPAL leukemia will vary depending on the diagnosis, age, and medical history. As MPAL leukemia is challenging to treat, the treatment plan is often intensive and usually starts quickly after diagnosis.

A 2018 systematic review and meta-analysis and a 2017 review both suggest that using a chemotherapy regimen for ALL or a combined ALL/AML regimen can result in a better outcome for people with MPAL leukemia than using chemotherapy that doctors use only for AML. A 2019 paper also suggests that ALL treatment may be preferable for treating MPAL.

A 2020 study notes that in cases of MPAL with a Philadelphia chromosome abnormality, the use of targeted therapy such as tyrosine kinase inhibitors can help to improve outcomes.

Doctors may consider other treatments if these options do not provide a satisfactory response. For example, they may use immunotherapies, which activate the immune system to detect and attack cancer cells. A doctor may also perform a stem cell transplant to eradicate any remaining leukemia cells in the bone marrow.

Historically, the outlook for individuals with MPAL has not been very positive. However, with more research and advances in treatment options, the outlook is improving. While it remains hard to predict the overall survival for those with MPAL, evidence suggests that factors that may predict a less positive outcome include:

A 2017 retrospective study suggested the three-year overall survival rate for MPAL was 56.3%, compared with the 5-year survival rate of 65% for leukemia in general. Like other acute leukemias, the quicker the diagnosis and treatment of MPAL, the higher the chance of recovery.

MPAL is a rare form of blood cancer that presents with clinical features of AML and ALL. As with other acute leukemias, the exact cause is unknown, but many cases are associated with genetic abnormalities. Due to its rarity and various diagnostic criteria, it can be a difficult condition to diagnose.

Treatment options vary depending on an individuals diagnosis, age, and medical history but may include chemotherapy, targeted therapy, immunotherapy, and stem cell transplants. While the outlook for MPAL is generally poorer than other leukemias, advances in research and treatments are improving outcomes.

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MPAL leukemia: Symptoms, diagnosis, and treatments - Medical News Today

Bone Marrow Stem Cells Comments Off on MPAL leukemia: Symptoms, diagnosis, and treatments – Medical News Today | March 22nd, 2022

Abbie Young was 16 when she was given the devastating news that her body was suffering from severe Aplastic Anaemia.

With her bone marrow failing, medics at Newcastles Royal Victoria Infirmary Ward 3 were in a race against time to find a stem cell donor who could give her a fighting chance.

Abbie, now 18, is on the road to recovery thanks to the Anthony Nolan Trust.

To say thank you for saving her life, the Harton Academy pupil is aiming to help boost the charitys work by hosting a fundraising day at school on Friday, April 8.

Abbie, who hopes to become an Anthony Nolan youth ambassador, is aiming to encourage others to sign up as stem cell donors and help save lives.

She said: I just feel really grateful that someone out there took the time to sign up to the stem cell register and that one choice someone made, has saved my life.

I know some kids die waiting for a donor, so I will always be forever grateful for what my donors did and to the Anthony Nolan Trust.

The teenager discovered her bone marrow was failing her after her mum became concerned over the number of bruises her daughter had. Abbie was diagnosed in January 2020.

Mum Caroline, 49, said: We went to the doctors who sent Abbie to South Tyneside Hospital for blood tests.

Abbie was at the hospital on the Friday (January 10), then by Saturday morning we had a knock on the door and there was an ambulance outside, they had come for Abbie.

They took us to Sunderland hospital and her dad followed up in the car, where they did more tests, they thought she had leukaemia, so we were transferred straight to the RVI.

According to information from Great Ormond Street Hospital, severe Aplastic Anaemia only affects around 30 to 40 children in the UK each year.

After Abbies older siblings, brother Sam, 26, and sister Kate, 21, were found not to be matches, a donor from Germany was found with the charitys help.

Abbies first transplant was in May 2020, but with the country in Covid lockdown, the stem cells had to be frozen due to restrictions.

The first transplant failed, believed in part due to the stem cells having been frozen.

The Anthony Nolan Trust stepped in and a second donor was found, but the cells were not frozen this time at the request of the hospital.

Caroline added: It is so hard when it's your child's life is suddenly put into the hands of a stranger. You're waiting for someone you don't know to come forward and help save your child's life.

The teenager underwent her second transplant in July 2020 and following a number of blood transfusions, the treatment started to work.

But due to complexities, she needed to have a top-up from her second donor at a later date.

Throughout Abbies treatment, which also included several doses of chemotherapy, radiotherapy and the top-up donation dose, she needed to stay confined in a bubble with only Caroline, dad Karl and nursing staff for company.

Abbie, of Beacon Glade, told the Gazette she felt like shed lost her purpose while receiving treatment and that losing her hair felt like the worst day of my life.

She explained: I was in denial about the whole thing. I knew I was bruising easily, but I didn't want to do anything about it. I was in denial about everything.

"I knew people lost their hair with treatment but I thought I'd be the one who didn't. Then I did and I was devastated.

I just felt like I had lost my purpose. When I lost my hair, it felt like the worst day of my life, I had had also put on quite a bit of weight.

Following her treatment and a number of blood and platelet transfusions, Abbie was finally able to ring the bell on leaving Ward 3 in August 2020; but she still needed to shield to give her body the best chance of survival.

Now, shes studying Biology, Chemistry and Psychology at A-Level and focusing on supporting the life-saving charity with her fundraising mission.

At time of writing and with weeks to go until her fundraising day at school more than 1,500 has been donated to her JustGiving page.

On her page, she said: Without you there is no cure. For someone with blood cancer, a stem cell transplant could be their last chance of survival.

Mum Caroline added: The hospital, the staff on Ward 3, were brilliant and the nurses were amazing. They were more like friends than medical professionals.

"At the time, you couldn't mix with anyone, so they were a good support to us as a family and to Abbie.

Abbie's school has also been supportive. Sir Ken, who is the school's executive head teacher, would call every day and ask how she was.

When it happened, teachers would drop off books for Abbie and they were even talking about a teacher going into a bubble, so that they could invigilate her for her GCSE exams. But the exams never happened because of Covid.

"We will be forever grateful for everyone's support.

Abbie and her family would like to thank the following companies who have donated prizes to help raise funds through a raffle or have donated to her JustGiving page. They include:

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'Without you there is no cure' - Teenager's call for stem cell donors in mission to support Anthony Nolan Trust - Shields Gazette

Bone Marrow Stem Cells Comments Off on ‘Without you there is no cure’ – Teenager’s call for stem cell donors in mission to support Anthony Nolan Trust – Shields Gazette | March 22nd, 2022

Hemolysis refers to the destruction of red blood cells (RBCs). Typically, RBCs can live for up to 120 days before the body naturally destroys them. However, certain conditions and medications may cause them to break down quicker than usual.

RBCs, or erythrocytes, are one of the main components of blood. They have the shape of a slightly indented, flattened disk and help transport oxygen to and from the lungs. The average life span of a healthy RBC is roughly 4 months.

Typically, the body will destroy old or damaged RBCs in the spleen or in other parts of the body through a process known as hemolysis.

Usually, the body is capable of quickly replacing RBCs, producing around 2 million blood cells every second. However, people may experience symptoms of anemia if the body has a low number of RBCs due to excessive hemolysis.

In this article, we discuss hemolysis in detail, including its potential causes and treatment options.

Hemolysis is the breakdown of RBCs. Some people may also refer to hemolysis by other names, such as hematolysis, erythrolysis, or erythrocytolysis.

Hemolysis is a natural bodily process that occurs when RBCs become too old. As RBCs age, they begin to lose certain properties and work less efficiently. For example, they may lose their deformability, which allows them to reversibly change shape to pass through blood vessels.

As RBCs begin to lose functionality, they accumulate signals that initiate erythrocyte turnover. The body typically performs hemolysis in the spleen. As blood filters through this organ, it is able to detect any old or damaged RBCs. Then, large white blood cells, or macrophages, break down these RBCs.

However, some conditions, medications, and toxins may cause RBCs to break down quicker than usual.

A doctor may measure a persons hematocrit levels. This refers to the percentage of RBCs in the body. A typical hematocrit level can vary depending on many factors, such as age and race. However, low levels may suggest a high turnover of RBCs.

There are many potential factors that may lead to hemolysis. The cause of hemolysis can be extrinsic, coming from an outside source, or intrinsic, which is when it comes from the RBC itself.

Extrinsic causes include certain conditions or outside factors that destroy RBC, such as:

Certain conditions may result in changes within the RBC itself, which can lead to hemolysis. This can include deformities in the cell structure and metabolism or in the hemoglobin structure.

These conditions may include:

Excessive hemolysis can lead to hemolytic anemia. This refers to a group of conditions that present with symptoms similar to those of other types of anemia, due to hemolysis occurring too fast or too often.

The condition can develop suddenly or slowly, and it can be mild or severe. Possible symptoms may include:

Symptoms of severe hemolytic anemia may include:

Hemolytic disease of the newborn, which health experts also call erythroblastosis fetalis, is a blood condition in which a rhesus (Rh) factor incompatibility occurs during pregnancy. This refers to a protein that may be present on the surface of RBCs.

If a person with Rh-negative blood becomes pregnant, and the fetus inherits Rh-positive blood from the persons partner, it can result in a harmful immune response. Around 13 in 1,000 people experience this reaction.

During pregnancy, blood from the fetus can cross the placenta and enter the parents blood. With Rh incompatibility, the parents immune system may recognize this blood as foreign material and produce antibodies against the Rh-positive blood.

This is more likely to occur after the first pregnancy, since the pregnant persons immune system will recognize the fetuss blood as foreign and have antibodies ready. If doctors detect this early, they can prevent this condition by giving the parent an Rh immunoglobulin (RHIg) to prevent their immune system from producing antibodies.

A person will receive RHIg as an injection at 28 weeks of pregnancy to prevent the production of antibodies, and within 72 hours of delivering the baby with Rh-positive blood to prevent the production of antibodies that could affect a future pregnancy.

AIHA is a rare condition in children, affecting 0.8 in 100,000 children under the age of 18 years. It can occur after a recent viral infection or after using certain drugs. It can also be due to some conditions.

The most common form of AIHA in children is due to warm-reactive antibodies. The term warm-reactive refers to the fact that optimal antigen binding occurs close to body temperature at 98.6F.

A 2021 study notes that a sudden presentation of AIHA is often life threatening and progresses quickly, requiring prompt diagnosis, treatment, and monitoring.

Initially, a doctor will review a persons symptoms and medical history and perform a physical examination.

If they suspect hemolytic anemia, they may request the following tests:

Treatment options will depend on the cause of hemolysis. Moreover, doctors will consider the following when creating a treatment plan:

Treatments may include:

The byproducts of RBC destruction can cause reactions that can damage multiple organs. Complications due to hemolytic anemia can include:

Arrhythmia, cardiomyopathy, heart failure, and iron deficiency are other possible complications.

It is advisable for a person to consult a doctor if they experience any of the following symptoms:

Hemolysis is a natural process where the body destroys older RBCs that no longer work efficiently. However, some conditions, medications, and toxins may cause RBCs to break down prematurely.

When this occurs, people may experience symptoms of anemia, such as fatigue, dizziness, and headaches. In other cases, symptoms can be more severe.

A person exhibiting early signs of anemia should consult a doctor for a prompt diagnosis and treatment.

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Hemolysis: Types, causes, and treatments - Medical News Today

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Emily Whitehead:

Emily Whitehead

Warriors come in all shapes and sizes. Take for example Emily Whitehead, as fresh-faced a 16-year-old as has ever graced the planet. Her eyes nearly sparkle with intellectual curiosity and dreams for a fulfilling future. But Emily is not a typical teen. She is the first pediatric patient in the world to receive CAR T-cell therapy for relapsed/refractory acute lymphoblastic leukemia (ALL). She is a singular figure in the annals of medicine. She is a soldier on the front lines of the war on cancer. And like the shot heard round the world, her personal medical assault sparked a revolution in cancer care that continues to power forward.

It has been 10 years since the only child of Thomas and Kari Whitehead of Philipsburg, PA, received an infusion of CAR T cells at the hands of a collaborative medical team from the Children's Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania. That team included, among others, luminary CAR T-cell therapy pioneer, Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine and Director of the Center for Cellular Immunotherapies at Penn's Perelman School of Medicine; as well as Stephan Grupp, MD, PhD, Professor of Pediatrics at the Perelman School of Medicine (at that time, Director of the Cancer Immunotherapy Program at CHOP) and now Section Chief for Cell Therapy and Transplant at the hospital. He had been working with June on cell therapies since 2000.

Tremendous progress has flowedgushedfrom the effort to save Emily Whitehead; many more lives have been saved around the globe since that fatefulyet nearly fatalundertaking. While all the progress that has come from this story must be our ultimate theme, it cannot be fully appreciated without knowing how it came to be.

In 2010, Emily, then 5 years old, went from a being a healthy youngster one day, to a child diagnosed with ALL. Chemotherapy typically works well in pediatric ALL patients; Emily was one of the exceptions. After 2 years of intermittent chemotherapy, she continued to relapse. And when a bone marrow transplant seemed the only hope left, her disease was out of control and the treatment just wasn't possible. The Whiteheads were told by her medical team in Hershey, PA, nothing more could be done. They were instructed to take Emily home where she could die peacefully, surrounded by family.

But peaceful surrender didn't interest the Whiteheads; they rejected any version of giving up. It ran contrary to Tom Whitehead's vision of her recovery, something he said was revealed to him in the whispers. He saw, in a prophetic whispering dream, that Emily would be treated in Philadelphia. More importantly, he saw she would survive. It is as if it happened yesterday, said Tom, remembering how unrelentingly he called doctors at CHOP and said, We're coming there, no matter what you can or cannot do. We're not letting it end like this.

Since we treated Emily, we have treated more than 420 patients with CAR T cells at CHOP. She launched a whole group to be treated with this therapy; thousands have been treated around the world.Stephan Grupp, MD, PhD

A combination of persistence and perfect timing provided the magic bullet. It was just the day before that CHOP received approval to treat their first pediatric relapsed/refractory ALL patient with CAR T cells in a trial. And standing right there, on the threshold of history, was that deathly sick little girl named Emily.

At that time, only a scant few terminal adult patients had ever received the treatment, which is now FDA-approved as tisagenlecleucel and developed in cooperation with CHOP and the University of Pennsylvania. When three adults were treated, two experienced quick and complete remission of their cancers. Could CAR T-cell therapy perform a miracle for Emily? A lot would ride on the answer.

On March 1, 2012, Emily was transferred to CHOP and a few days later an apheresis catheter was placed in her neck; her T cells were extracted and sent to a lab. Emily received more chemotherapy, which knocked out her existing immune system, and she was kept in isolation for 6 weeks. Waiting.

Finally, over 3 days in April, Emily's re-engineered T cells, weaponized with chimeric antigen receptors, were infused back into her weakening body. But Emily did not rise like a Phoenix from the ashes of ALL. Instead, she sunk into the feverish fire of cytokine release syndrome (CRS), and experienced a worse-than-anticipated reaction. The hope for a swift victory seemed to be disappearing.

I can still see Emily's blood pressure dropping down to 53/29, her fever going up to 105F, her body swelling beyond recognition, her struggle to breathe, said Tom, of the most nightmarish period of his life. Doctors induced a coma, and Emily was put on a ventilator. For 14 days, her death seemed imminent. Doctors told us Emily had a one in a thousand chance of surviving, said Tom. They said she could die at any moment. But she didn't.

Medical team members who fought alongside the young patient are unwavering heroes in Emily's story. But at the time of her massive struggle, they too were exhausted and battle-scarred, descending into the quicksand of what could have been a failing trial, grasping for some life-saving branch of stability. They knew if CRS could be overcome, the CAR T cells might work a miracle as they had done for those earlier adult patients. But the CRS was severe. There was no obvious antidote; time was running out.

I recall Dr. June saying he believed Emily was past the point where she could come back and recover, said her father. And he said if she didn't turn around, this whole immunotherapy revolution would be over.

The Whiteheads enjoy Penn State football games not far from their hometown. The family has often taken part in Penn State's THON, a 48-hour dance marathon that raises funds for childhood cancer.

June confirmed to Oncology Times that he and Grupp believed Emily would not survive the night. It was mentioned to the Whiteheads that perhaps they should just concentrate on comfort care measures and stop all the ICU interventions, he recalled. I believed she was going to die on the trial due to all the toxicity. I even drafted a letter to our provost to give a heads up.

When the first patient in a trial dies, that's called a Grade 5 toxicity, June noted. That closes the trial as well. It goes right into the trash bin and you have to start all over again. But fortunately, that letter never left my outbox. We decided to continue one more day, and an amazing event happened.

Grupp, offering context to the mysterious amazing event, said it was clear that Emily's extreme CRS was caused by the infusion of cells that he himself had placed in her fragile body. He said he felt an enormous sense of responsibility and incredible urgency as he watched the child struggle to live.

It was not until the CHOP/Penn team received results from a test profiling cytokines in Emily's body that a new flicker of hope sparked. Though Emily had many cytokine abnormalities, the one most strikingly abnormal, interleukin-6 (IL-6), caught the team's attention. It is not made by T cells, and should not have been part of the critical mix. Though there were very few cytokines that had drugs to target them individually, IL-6 was one that did. So the doctors decided to repurpose tocilizumab, an arthritis drug, as a last-ditch effort at saving their young patient.

We treated Emily with tocilizumab out of desperation, June admitted. Steve [Grupp] has told me that when he went to the ICU with tocilizumab as a rescue attempt for CRS, the ICU docs called him a cowboy. The ICU docs had given up hope for Emily. But she turned aroundunbelievably rapidly. Today, tocilizumab is the standard of care for CRS, and the only drug approved by the FDA for that complication. Emily's recovery was huge for the entire field.

Grupp reflected on the immensity of the moment. If things had gone differently, if Emily had experienced fatal toxicity, it would have been devastating to her family and to the medical team. And it might have ended the whole research endeavor. It would have set us back years and years. The impact that Emily and her family had on the field is nothing short of transformational, he declared.

Since we treated Emily, we have treated more than 420 patients with CAR T cells at CHOP. She launched a whole group to be treated with this therapy; thousands have been treated around the world, Grupp noted. And, if not for Emily, we wouldn't be in the position we are in todaywith five FDA-approved [CAR T-cell] products: four for adults and one for kids. And I think it also important to point out that the very first CAR-T approval, thanks to Emily, was in pediatric ALL.

June noted that between 2010 and the time of Emily's treatment in 2012, My work was running like a shoestring operation. I had to fire people because I couldn't get grants to support the infrastructure of the research. It was thought there was no way beyond an academic enterprise to actually make customized T cells, then mail and deliver them worldwide, he recalled.

But then everything changed. We experienced that initial success; it was totally exciting. It was a career-defining moment and the culmination of decades of research. It led to a lot of recognition, both for my contribution and for the team here at the University of Pennsylvania and at CHOP.

Today, hundreds of pharmaceutical and biotech companies are developing innovations. Hundreds of labs are making next-generation approaches to improve in this area, June noted. Today, I'm a kid in a candy shop because all kinds of things are happening. We have funding thanks to the amazing momentum from Emily. She literally changed the landscape of modern cancer therapy.

Grupp said the continuing CAR T-cell program at CHOP offers evidence of success in a broad perspective. There are two things to look at, he offered. The first is how well patients do with their therapy in terms of getting into remission. A month after getting their cells, are they in remission or not? A study with just CHOP patients showed that more than 90 percent met that bar (N Engl J Med 2014; doi: 10.1056/NEJMoa1407222). Worldwide, the numbers appear to be in the 80 percent range (N Engl J Med 2018; doi: 10.1056/NEJMoa1709866). So, I would say it is a highly successful therapy.

We now have trials using different cell types, like natural killer cells, monocytes, and stem cells, noted Carl June, MD, at Penn's Perelman School of Medicine. An entirely new field has opened because of our initial success. This is going to continue for a long time, making more potent cells that cover all kinds of cancer.

The other big question, Grupp noted: How long does remission last? We are probably looking at about 50 percent of patients remaining in remission long-term, which is to say years after the infusion. The farther out we go, the fewer patients there are to look at because it just started with Emily in 2012, reminded Grupp. We have Emily now 10 years out, and other patients who are at 5, 6, 7, 8 years out, but most were treated more recently than that. We need to follow them longer.

June said registries of patients treated with CAR T-cell therapy are being kept worldwide by various groups, including the FDA. CAR T-cell therapy happened fastest in the U.S., but it's gained traction in Japan, Europe, Australia, and they all have databases. The U.S. database for CAR T cells will probably be the best that exists, because the FDA requires people treated continue follow-up for at least 15 years, he explained.

This will provide important information about any long-term complications, and the relapse rate. If patients do get cancer again, will it be a new one or related to the first one we treated? We will follow the outcomes, he noted. Clinicians are teaching us a lot about how to use the informationat what stage of the disease the therapy is best used, and which patients are most likely to respond. This can move us forward.

June mentioned that Grupp is collaborating with the Children's Oncology Group ALL Committee led by Mignon Loh, MD, at the University of California in San Francisco.

They are conducting a national trial to explore using CAR T cells as a frontline therapy in newly diagnosed patients, he detailed. Emily was treated when she had pounds and pounds of leukemia in her body; ideally we don't want to wait so long. There are a lot of reasons to believe it would work as a frontline therapy and spare patients all the complications of previous chemotherapy and/or radiation. The good news is that the clinical trial is under way, and I suspect we may know the answer within 2 years.

The only true measure of success in Emily's case is the state of her health. When asked if she is considered cured, June said, All we can do is a lot of prognostication. We know with other therapies in leukemia, the most similar being bone marrow transplants, if you go 5 years without relapsing, basically you are considered cured. We don't know with CAR T cells because Emily is the first one. We have no other history. But she's at a decade now, and in lab data we cannot find any leukemia in her. So by all of the evidence we haveand by looking in the magic eight ballI believe Emily is cured.

One might think that going through such a battle for life would be enough for any one person, any one family. But for Emily and her parents, her survival was just the beginning of a larger assault. All of them saw the experience as a way to provide interest in continuing research, education for patients as well as physicians, and an extension of hope to other patients about to succumb to a cancerous enemy.

Tom thought back to one particular occasion, all those years ago, when Emily finally slept peacefully through the night in her hospital bed. I should have felt nothing but relief, but I heard a mother crying in the hallway. Her child, who has been in the room next door, had died that morning, he recalled. I am constantly reminded of how fortunate we are. There are so many parents fighting for their children who do not have a good outcome.

As soon as Emily regained her strength and resumed normal childhood activities, the family began travelling with members of the medical team, joining in presentations at meetings and conferences throughout the world. They wanted to give a human face to the potential of CAR T-cell therapy, and as such they willingly became a powerful tool to raise understanding and essential research dollars. In 2016, the Whiteheads founded the Emily Whitehead Foundation (www.emilywhiteheadfoundation.org) ...to help fund research for new, less toxic pediatric treatments, and to give other families hope.

We decided to hold what we called the Believe Ball in 2017. We asked lots of companies to sponsor a child who had received CAR T-cell treatment to come with their family to the ball at no cost to them. Each company's representative would be seated with the child and family they sponsored, and would meet the doctors and scientists involved in the research, as well as members of industry and pharma, to see exactly where research dollars are going. We implored these companies to move the cancer revolution forward with sponsorship. When it all shook out, we had around 35 CAR T-cell families together for the first time, said Tom.

He noted proudly that since the foundation's debut, donations have been consistent and now have totaled an impressive $1.5 million.

When the Emily Whitehead Foundation had a virtual gala recently, it awarded a $50,000 grantthe Nicole Gularte Fight for Cures Ambassador Awardto a young researcher working to get another trial started. The award is named for a woman who found her way to CAR T-cell trials at Penn through the Whitehead Foundation. The treatment extended her life by 5 years during which time Gularte became an advocate for other cancer patients, travelled with the Whiteheads, and made personal appearances whenever she thought she could be of help or inspiration. Eventually, she would relapse and succumb, but she assured Tom Whitehead, These were 5 of the best years of my life. I think my time here on Earth was meant to help cancer research move forward.'

While raising funds for progress is important, the Whiteheads' work is not just about bringing in money. It's also about education.

We want to send a message to all oncologists; they need to be more informed about these emerging treatments when their patients ask for help, Tom noted. In the beginning of CAR T-cell therapy, a lot of doctors were against it. It's hard to believe, but some still are, though not as much. We need more education so that oncologists give patients a chance to get to big research hospitals for cutting-edge treatments before everything else has failed.

June said he regularly interacts with patients Tom or the foundation refer to him. Such unawareness happens with all new therapies, he noted. The people most familiar with them are at academic medical centers. But only about 10 percent of patients actually go to academic centers, the rest are in community centers where newer therapies take much longer to roll out, he explained.

So much of Emily's life has been chronicled through the eyes of observers. But since her watershed medical intervention, she has grown into a well-travelled, articulate young woman who talks easily about her life. I used to let my father do all the talking, but I am finding my own voice now, she said, having granted an interview to Oncology Times.

I'm currently 16 years old and I'm a junior at high school. Just like when I was younger, cows are my favorite animals, she offered with a laugh. I still love playing with our chihuahua, Luna. In school, I love my young adult literature class because I really like reading. Besides that, I like art and film. And I'm in really good health today.

She mentioned her health casually, almost as an afterthought. I really don't have any memory of my treatment at this point, she revealed, but, the experiences that I've had since then have really shaped who I am. Traveling is a huge part of my life now and something I look forward to. We've been to conferences at a lot of distant places. I'm so grateful that I get to travel with my family and make these memories that I will have forever, while still being able to advocate for less toxic treatment options and raising money for cancer research. All of that is really important to me.

Reminded that she has already obtained fame as pediatric patient No. 1 for CAR T-cell therapy, Emily considered her status for a moment then commented, I don't really like to base the progress of the therapy on my story and what I went through. Instead, I like to take my experience and use it to advocate for all patients so that what happened to me does not have to be repeated and endured by another family. My hope is that CAR T-cell therapy will become a frontline treatment option and be readily available, so pediatric patients can get back to a normal life as soon as possible. I want to tell people if conventional treatments do not work, other options do exist. Overall, I am grateful that I can encourage others to keep fighting. That's the main thing; I am grateful.

After a brief pause, Emily continued, I always tell oncologists and scientists that the work they are doing is truly saving children's lives. It allows these kids to grow up, be with their friends and families, take vacations, play with their dogs, and someday go to college, just like me. They are not only saving patients' lives, they are saving families. The work they do does not go unnoticed or unappreciated. Again, I am really so grateful.

Appreciation is a two-way street, and June said he and his team appreciate and draw inspiration from Emily on a daily basis. Her picture hangs on the wall of our manufacturing center, June stated. Some of the technicians who were in high school when Emily was infused are now manufacturing CAR T cells. They learned so much from Emily's experience; she continues to be a big motivator. She's helped my team galvanize and see that the work can really benefit people.

Grupp said the success that is embodied in Emily Whitehead has spurred additional successes, and new inroads in CAR T-cell therapy. There are more applications now, especially in other blood cancerslymphoma and myeloma, in addition to leukemia. We've seen a lot of expansion there.

He noted a national trial is under way for an FDA-approved therapy called idecabtagene vicleucel, which can benefit multiple myeloma patients. All other CAR Ts target the same target, CD19. But this goes after an entirely different target, BCMA. The fact that we now have approval in something that isn't aimed at CD19 is very exciting. And there are others coming right behind it.

The field also has seen further expansion ...into adults being treated safely, because initially there was concern that these drug therapies were too powerful for safe treatment in older adults, detailed Grupp. Now we know that is clearly not the case, and that is great news, particularly because multiple myeloma most often occurs in people over 60.

The use of CAR T cells in solid tumors continues to be challenging, although Grupp noted, We have certainly seen hints of patients with solid tumors having major responses and going into remission with CAR T cells. It is still a small handful of patients, so we haven't perfected the recipe for solid tumors yet. But I am absolutely confident we will have the answers in a very short numberperhaps 2-4of years.

June said, since Emily's infusion, CAR T cells have matured and gotten better. There are many ways that has happened, he informed. We have different kinds of CAR designs to improve and increase the response rates, to decrease the CRS, or to target other kinds of bone marrow cancers. One that is not curable with a lot of therapies is acute myeloid leukemia (AML), so we have a huge group at Penn and CHOP working on AML specifically. And there is the whole field of solid cancer; we have teams working on pancreatic, prostate, breast, brain, and lung cancer now.

In addition to targeting different types of cancer, June said contemporary research is also exploring the use of different types of cells. Our initial CAR T trial used T cells, and that is what all the FDA-approved CARs are. But we now have trials using different cell types, like natural killer cells, monocytes, and stem cells. An entirely new field has opened because of our initial success. This is going to continue for a long time, making more potent cells that cover all kinds of cancer, not just leukemia and lymphoma.

Is this the beginning of the end of cancer? Is this that Holy Grail called a cure to cancer? It's a question June has pondered.

Some people do think that, he answered. They believe the immune system is the solution. And that's a huge statement. President Biden has made a big investment in this work, with the Cancer Moonshot. He's accelerated this research at the federal level. But we just don't know how long it is going to take. Fortunately, a lot of good minds are working hard to make an end to cancer a reality.

As the battle grinds on, June said he applies something he's learned over time, with reinforcement from Tom and Kari Whitehead. They were bulldogs. When it came to getting treatment for Emily, they just wouldn't take no for an answer. They demonstrated the importance of never giving up. That's what happened; they would not surrender. I think that is why Emily is alive today.

Valerie Neff Newitt is a contributing writer.

The Emily Whitehead Foundation and the Whitehead family take extraordinary advantage of a variety of media to reach patients and physicians and optimize educational opportunities.

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The Incredible Story of Emily Whitehead & CAR T-Cell Therapy : Oncology Times - LWW Journals

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Despite progress involving the use of induced pluripotent stem cells (iPSCs) within disease modeling and drug discovery applications, it will be a long path to achieve the broad-scale use of iPSC-derived cell types in human patients.

Within a preclinical context, cell types differentiated from iPSCs are tested for their therapeutic response. Then, clinical trials are conducted to assure that essential parameters, such as tumorigenicity, dose toxicity, and immunogenicity, are assessed before authorizing the product for use in human patients. iPSC-derived cells have the potential to be used as therapies for treating cardiovascular, neurological, and metabolic diseases, as well as repairing damaged cartilage, spinal, motor neuron and eye tissues resulting from genetic defects or injuries.

In general, the targets for iPSC-derived therapies include any diseases or disorders for which there are no other viable treatments and where there is a need to repair or replace dysfunctional tissue.

Today, the following companies and organizations are forging the path toward iPSC-derived cell therapeutics.

While the groups above are involved with the development of iPSC-based cell therapeutics, not all of them have reached clinical-stage. Companies and organizations developing clinical-stage iPSC-derived therapeutics are described below.

In 2016, Cynata Therapeutics received a landmark approval to launch the worlds first formal clinical trial of an allogeneic iPSC-derived cell product (CYP-001) for the treatment of GvHD. In collaboration with Fujifilm, Cynata Therapeutics completed this Phase I trial in December 2018, reporting positive results.

Cynata Therapeutics is now testing its product candidate CYP-004 in a Phase 3 clinical trial enrolling up to 440 patients. CYP-004 is an allogeneic, iPSC-derived mesenchymal stem cell (MSC) product derived using Cynatas proprietary Cymerus technology. Led by the University of Sydney and funded by the Australian Government National Health and Medical Research Council (NHMRC), the trial will assess whether the cells can improve patient outcomes in osteoarthritis (OA).

It will be the worlds first clinical trial involving an iPSC-derived cell therapeutic to enter Phase 3 and the largest one ever completed.

In December 2019, the National Institutes of Health (NIH) announced it would be undertaking the first U.S. clinical trial of an iPSC-derived therapeutic. The goal of this trial is to restore dying cells of the retina. The Phase I/IIa clinical trial involves 12 patients with advanced-stage geographic atrophy who received an iPSC-derived retinal pigment epithelial (RPE) implant into a single eye. This trial is supported by the Ocular and Stem Cell Translational Research Section of the National Eye Institute (NEI). The NEI is part of the NIH.

In February 2019, allogeneic iPSC-derived NK cells produced by scientists from the University of Minnesota in collaboration with Fate Therapeutics were granted approval by FDA for a clinical trial. Specifically, Fate Therapeutics is exploring the clinical use of FT516 and FT500, which are its off-the-shelf, iPSC-derived natural killer (NK) cell product candidates. In December 2019, the company released promising clinical data from its Phase 1 studies.

In July 2020, Fate Therapeutics subsequently announced FDA clearance of its IND application for the worlds first iPSC-derived CAR T-cell therapy, FT819.FT819 is an off-the-shelf allogeneic chimeric antigen receptor (CAR) T-cell therapy targeting CD19+ malignancies. Notably, the use of a clonal master iPSC line as the starting cell source will position Fate to mass produce CAR T-cells to be delivered off-the-shelf to patients.

The Japanese company Healios K.K. is preparing, in collaboration with Sumitomo Dainippon Pharma, for a clinical trial using allogeneic iPSC-derived retinal cells to treat age-related macular degeneration (AMD).

Of course, there are also numerous physician-led studies underway in Japan investigating the use of iPSC-derived cellular products inhuman patients. These clinical trials are for diseases such as macular degeneration, ischemic cardiomyopathy, Parkinsons disease, solid tumors, spinal cord injury (SCI) and platelet production.

Details on each of these Japanese trials are provided below:

Significant progress has been made for retinal degeneration diseases, particularly for age-related macular degeneration (AMD). In 2009, preclinical data showed for the first time the recovery of visual function in patients injected with retinal pigment epithelium (RPE) differentiated from iPSCs in a rat models retina. A major breakthrough was made when the group led by Masayo Takahashi at the Riken Centre for Developmental Biology in Japan produced iPSC-RPE cell sheets in 2014.

The above-mentioned successes led to the initiation of the first iPSCs clinical trial in 2014 itself. Scientists at the RIKEN Centre in Japan transplanted an autologous iPSC-RPE cell sheet just below the affected retina, without immunosuppression, in a 77-year-old woman with AMD. One year after the transplantation, the progression of the degeneration simply halted, an area with photoreceptors recovery was observed, and the patients vision remained stable. There were no symptoms of immune rejection or tumor development.

In March 2017, Japanese scientists announced that a 60-year-old man was the first patient to receive iPSC-RPE cells derived from another person (an allogeneic source). A clinical-grade iPSC bank for collecting and storing healthy HLA homozygous donors is now being established at the Centre for iPS Cell Research and Application (CiRA) in Kyoto (Japan).

Also in 2017, iPSC-derived cardiomyocytes were grafted on to a porcine model of ischemic cardiomyopathy by Kawamura, et al., using a cell-sheet technique. Cardiac function was significantly improved, and neovasculogenesis was observed. Recently, scientists from Osaka University were granted approval for a clinical trial to transplant allogeneic sheets of tissue derived from iPSCs onto the diseased hearts of three human patients.

Several preclinical studies in spinal cord injuries using iPSC-derived neural progenitor cells in animal models have provided evidence for remyelination and locomotor function recovery. In February 2018, the Japanese government gave an approval to Professor Hideyuki Okano for a clinical trial that will involve the treatment of patients with spinal cord injuries at Keio University.

In September 2018, group of scientists from Kyoto University were granted approval to begin a transfusion trial using platelets derived from iPSCs into an individual with aplastic anemia. The hope is that iPSC-derived platelets could replace transfusions of donated blood.

As early as 2008, it was confirmed that iPSC-derived dopaminergic neurons improved the symptoms and dopaminergic function of a rat model of Parkinsons disease. Approximately a decade later, in October 2018, dopamine precursor cells were created from allogeneic iPSCs produced by Jun Takahashis research group at Kyoto University. Physicians at Kyoto University Hospital then transplanted these cells into subjects with Parkinsons disease. A total of seven patients were involved.

In July 2019, scientists at Osaka University started a clinical trial for limbal stem cell deficiency, a condition in which corneal stem cells are lost. The scientists grafted a sheet of iPSC-derived corneal cells onto the cornea of a patient. Within one month, her vision seemed to have improved.

What questions do you have about the development of iPSC-derived cell therapeutics? Ask them in the comments below.

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The Pipeline for of iPSC-Derived Cell Therapeutics in 2022 ...

IPS Cell Therapy Comments Off on The Pipeline for of iPSC-Derived Cell Therapeutics in 2022 … | March 22nd, 2022

Theranostics. 2020; 10(8): 36223635.

Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673, Singapore

Competing Interests: The authors have declared that no competing interest exists.

Received 2019 Oct 4; Accepted 2019 Dec 20.

The transcriptional co-regulators YAP and TAZ pair primarily with the TEAD family of transcription factors to elicit a gene expression signature that plays a prominent role in cancer development, progression and metastasis. YAP and TAZ endow cells with various oncogenic traits such that they sustain proliferation, inhibit apoptosis, maintain stemness, respond to mechanical stimuli, engineer metabolism, promote angiogenesis, suppress immune response and develop resistance to therapies. Therefore, inhibiting YAP/TAZ- TEAD is an attractive and viable option for novel cancer therapy. It is exciting to know that many drugs already in the clinic restrict YAP/TAZ activities and several novel YAP/TAZ inhibitors are currently under development. We have classified YAP/TAZ-inhibiting drugs into three groups. Group I drugs act on the upstream regulators that are stimulators of YAP/TAZ activities. Many of the Group I drugs have the potential to be repurposed as YAP/TAZ indirect inhibitors to treat various solid cancers. Group II modalities act directly on YAP/TAZ or TEADs and disrupt their interaction; targeting TEADs has emerged as a novel option to inhibit YAP/TAZ, as TEADs are major mediators of their oncogenic programs. TEADs can also be leveraged on using small molecules to activate YAP/TAZ-dependent gene expression for use in regenerative medicine. Group III drugs focus on targeting one of the oncogenic downstream YAP/TAZ transcriptional target genes. With the right strategy and impetus, it is not far-fetched to expect a repurposed group I drug or a novel group II drug to combat YAP and TAZ in cancers in the near future.

Keywords: TEAD, YAP, TAZ, Hippo, cancer therapy

The transcriptional co-regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are key players that mediate various oncogenic processes and targeting their activities has emerged as an attractive option for potential cancer therapy. YAP, as the name suggests, was initially identified as a protein that associates with Yes, a src family kinase (SFK) 1. The exact function of YAP remained elusive until it was demonstrated to be a potent transcriptional activator 2. YAP's paralog TAZ, identified from a screen for 14-3-3 interacting proteins, is also a transcriptional co-activator 3 (Figure ).

The oncogenic milestones of the transcriptional co-regulators YAP and TAZ. Discovery of YAP/TAZ and TEAD functions predate the discovery of the Hippo pathway. Role of YAP/TAZ in the Hippo pathway and the discovery of their oncogenic abilities in cell and animal models are considered significant. The initial studies from the groups that linked YAP/TAZ to oncogenic signaling pathway, stemness, actin cytoskeleton, fusion genes, drug resistance, metabolism, angiogenesis and immune suppression are also listed.

YAP and TAZ do not have a DNA-binding domain and they need to associate with a transcription factor in order to access DNA. It has now emerged that YAP/TAZ use predominantly the TEAD (TEA domain) family of transcription factors 4 to elicit most of their biologically relevant gene expression programs. ChIP-Seq data unraveled a significant overlap in YAP/TAZ and TEAD peaks throughout the genome, and also showed that some YAP/TAZ-responsive genes are also synergistically regulated by AP-1 transcription factors 5, 6. In addition to its interaction with TEADs, YAP/TAZ also communicates with the mediator complex and chromatin modeling enzymes like the methyltransferase and SWI/SNF complex to elicit changes in gene expression 7-9. YAP/TAZ also suppress gene expression and should be regarded as co-regulators rather than co-activators 10.

YAP/TAZ are now considered as effectors of a physiologically and pathologically important signaling pathway - popularly called the Hippo pathway 11. The Hippo pathway was initially identified in a genetic mosaic screen in Drosophila but the pathway components are evolutionarily conserved. It is now known that the primary function of the Hippo pathway is to suppress the activity of Yorkie - the Drosophila homolog of YAP 12. The Hippo pathway in mammals also inhibits YAP/TAZ through phosphorylation by the large tumor suppressor (LATS) family of Hippo core kinases 13, which leads to cytoplasmic sequestration via interaction with 14-3-3 proteins and/or degradation via ubiquitin proteasome pathway 14, 15.

YAP and TAZ were first shown to transform mammary epithelial cells 16, 17. The oncogenic role of YAP became apparent when it was shown to be a driver gene in a mouse model of liver cancer 18 (Figure ). In a conditional transgenic mouse model, YAP overexpression dramatically increases liver size and the mouse eventually develops hepatocellular carcinoma 19, 20. In addition to causing primary tumor growth, YAP also helps in the metastatic dissemination of tumor cells 21.

Over a decade of research has revealed that YAP/TAZ integrates the inputs of various oncogenic signaling pathways, such as EGFR, TGF, Wnt, PI3K, GPCR and KRAS. Through expression of the ligand AREG, YAP was first shown to communicate with the EGFR pathway 22 (Figure ). The genes regulated by YAP/TAZ collectively coordinate various oncogenic processes, such as stemness, mechanotransduction, drug resistance, metabolic reprogramming, angiogenesis and immune suppression (Figure ), many of which are considered to be cancer hallmarks 23.

YAP and TAZ regulate the expression of crucial transcription factors like Sox2, Nanog and Oct4 and are able to maintain pluripotency or stemness in human embryonic stem cells (ESCs) and in induced pluripotent stem (iPS) cells 24, 25 (Figure ). More specifically, TAZ has been shown to confer self- renewal and tumorigenic capabilities to cancer stem cells 26. Within the microenvironmental landscape of tissues, YAP/TAZ are increasingly recognized as mechanosensors that respond to extrinsic and cell-intrinsic mechanical cues. To this end, mechanical signals related to extracellular matrix (ECM) stiffness, cell morphology and cytoskeletal tension rely on YAP/TAZ for a mechano-activated transcriptional program 27-29. YAP/TAZ target genes, CTGF and CYR61, cause resistance to chemotherapy drugs like Taxol 30 and YAP/TAZ has emerged as a widely used alternate survival pathway that is adopted by drug-resistant cancer cells 31. YAP/TAZ activity is regulated by glucose metabolism and is connected to the activity of the central metabolic sensor AMP-activated protein kinase (AMPK) 32-35. YAP/TAZ reprograms glucose, nucleotide and amino acid metabolism in order to increase the supply of energy and nutrients to fuel cancer cells 36. Through expression of proangiogenic factors like VEGF and angiopoetin-2 37, 38, YAP is able to stimulate blood vessel growth to support tumor angiogenesis 39. YAP is also shown to recruit myeloid-derived suppressor cells in prostate cancers in order to maintain an immune suppressive environment 40. Active YAP also recruits M2 macrophages to evade immune clearance 41.

A TAZ fusion gene (TAZ-CAMTA1) alone, in the absence of any other chromosomal alteration or mutation, is sufficient to drive epithelioid hemangioendothelioma (EHE), a vascular sarcoma 42, 43. Furthermore, comprehensive analysis of human tumors across multiple cancer types from the TCGA database unraveled that YAP and TAZ are frequently amplified in squamous cell cancers in a mutually exclusive manner 44. In human cancers, there is also a good correlation between YAP/TAZ target gene signature and poor prognosis. To date, a proportion of every solid tumor type has been shown to possess aberrant YAP/TAZ activity. Further, many of the upstream Hippo components that negatively regulate YAP/TAZ are found inactivated across many cancer types 45. Thus, all of this paint a clear picture of the prominent role played by YAP and TAZ at the roots of cancers 46, 47.

There are more than fifty drugs that have been shown to inhibit YAP/TAZ activity 48, however, with the exception of verteporfin; none act directly on YAP/TAZ. The unstructured nature of YAP and TAZ renders them difficult to target using small molecules. Therefore, YAP/TAZ inhibition is achieved indirectly through targeting their stimulators or partners. In this review, we focus on small molecules, antibody and peptide-based drugs, as the majority of the drugs in the clinic belong to this class. Less attention is given to nucleotide-based molecules and to small molecule YAP/TAZ inhibitors whose targets are unknown. We classify the YAP/TAZ-inhibiting drugs into three groups with each group having its own combating strategy to counter YAP/TAZ activity (Figure ). Group I drugs target the upstream YAP/TAZ stimulators and enhance the LATS-dependent inhibitory phosphorylation of YAP/TAZ in order to restrain their transcriptional output. Group II drugs/candidates act directly on YAP/TAZ or TEAD and may either interfere with the formation of the YAP/TAZ-TEAD complex or inhibit TEADs directly and hence affect YAP/TAZ-TEAD transcriptional outcomes. Group III drugs' combat strategy is to target the oncogenic proteins that are transcriptionally upregulated by YAP and TAZ.

Classification ofYAP/TAZ-TEAD inhibiting drugs into three groups. Group I drugs (red font) act upstream and prevent the nuclear entry of YAP and TAZ, group I drug targets for potential pharmacological exploitation in order to generate repurposed YAP/TAZ-inhibiting drugs are circled. Group II drugs (green font) disrupt the formation of the YAP/TAZ-TEAD complex and they primarily bind to the TEAD family of transcription factors. Group Ill drugs (blue font) act on the downstream transcriptional targets in order to prevent YAP/TAZ-mediated oncogenicity.

Group I drugs target the upstream proteins (Figure ), inhibition of which culminates in the enhancement of the LATS-dependent inhibitory phosphorylation of YAP/TAZ 49, 50. However, some group I targets like SFKs 51-53, AMPK 33, 34 and phosphatases 54-56 act directly on YAP and TAZ and activate them. Majority of group I drugs are kinase inhibitors, in addition to restricting YAP/TAZ nuclear entry; they intriguingly promote TAZ, but not YAP degradation. A possible explanation for this is the presence of two phosphodegrons that render TAZ more prone to degradation 15. Some group I drugs, such as MEK/MAPK inhibitors 57, 58 and -secretase inhibitors (GSIs) 59 have the ability to actively reduce both YAP and TAZ levels. HDAC inhibitors however, reduce YAP, but not TAZ levels 60. Here, we have classified the group I drugs based on the nature of the drug target.

Drugs targeting the EGFR, GPCR, Integrin, VEGFR and adenylyl cyclase families as well as those targeting receptors like the -secretase complex and Agrin are shown to inhibit YAP/TAZ activity 51, 61-64.

YAP/TAZ exploits the transformative abilities of the ErbB receptors (EGFR family) to drive cell proliferation. By transcribing ErbB ligands, such as AREG 22, 65, TGF- 66, NRG1 67 as well as the ErbB receptors EGFR and ErbB3 67, YAP is able to activate ErbB signaling and promote tumorigenesis. Sustained EGFR signaling also disassembles the Hippo core complexes leading to an increased active pool of YAP/TAZ 68 that is ready to transcribe more ErbB ligands/receptors. Under these conditions, EGFR inhibitors like Erlotinib 22 and AG-1478 66 (Figure ) are able to act as YAP/TAZ inhibitors and may be used for EGFR-driven cancers requiring YAP/TAZ transcription.

Signaling from G-protein coupled receptors (GPCRs), transduced by the associated G subunit or by the G subunits, modulates YAP/TAZ activities 69. Inhibiting Gq/11 sub-type signaling, using losartan 70, or stimulating Gs sub-type, using dihydrexidine, has been shown to stimulate YAP inhibitory phosphorylation 69. Agonism of Gs has been recently exploited to facilitate YAP/TAZ inhibition that reverses fibrosis in mice 71. G inhibition using gallein has also been shown to restrict YAP/TAZ 72. Activating mutations in the Gq/11 types of GPCRs present in approximately 80% of the uveal melanoma patients generate an active pool of YAP 73, 74 but the signal transduction occurs via Trio-Rho/Rac signaling and not through the canonical Hippo pathway 74.

Integrin signaling negatively regulates the Hippo pathway complexes to drive YAP/TAZ activity 75, 76. Although blocking integrin activity using RGD peptides 63, cilengitide (cyclic RGD peptide) 77, function-blocking antibodies - BHA 2.1 76 and clone AIIB2 78 has been shown to increase YAP/ TAZ's inhibitory phosphorylation, disappointingly, the efficacy of integrin- blocking drugs against cancers has not been clinically proven 79. Interestingly, a function-blocking antibody against Agrin, an extrinsic stimulator of integrin signaling, abrogates YAP-dependent proliferation in mouse models 63, 80.

Among the kinase inhibitors tested in a biosensor screen for LATS activity, the VEGFR inhibitors are shown to potently activate LATS and thereby inhibit YAP and TAZ activity 81. Further, VEGFR2 signaling is also shown to induce actin cytoskeletal changes and promote YAP/TAZ activation 82. Therefore, VEGFR inhibitors like SU4312, Apatinib, Axitinib and pazopanib are able to inhibit the expression of YAP/TAZ-responsive genes in endothelial cells. But whether these drugs work as YAP/TAZ inhibitors in cancer cells remains to be seen.

Enhancing cyclic AMP (cAMP) levels using the adenylyl cyclase activator forskolin activates the LATS kinases through Protein kinase A (PKA) and Rho 69, therefore forskolin is also a YAP/TAZ inhibitor. cAMP is degraded by the cyclic nucleotide phosphodiesterases (PDE), the use of PDE inhibitors like theophylline, IBMX, ibudilast and rolipram also promotes YAP/TAZ-inhibitory phosphorylation 83, 84.

Notch and YAP/TAZ signaling are also closely linked, inhibiting notch activity by targeting the -secretase complex, either using DAPT or dibenzazepine has been shown to decrease YAP/TAZ expression levels in mouse livers and also reduce YAP activation and YAP-induced dysplasia in the intestine 20, 51, 59.

Integrin signaling activates focal adhesion kinase (FAK), SFK and integrin- linked kinase (ILK). Growth factor and GPCR signaling occurs through mitogen-activated protein kinase (MAPK) and phosphoinositide 3-OH kinase (PI3K) signaling. There is also significant crosstalk in the signaling from these membrane receptors. Given the availability of potent small molecule drugs targeting the downstream kinases, they are leveraged on to inhibit YAP or TAZ activities.

Members of downstream integrin signaling pathway including FAK, its counterpart PYK2, and ILK have emerged as negative regulators of the core Hippo pathway and thus activate YAP/TAZ. Membrane receptors, such as ErbB and GPCRs are unable to activate YAP upon genetic deletion of ILK. Therefore, pharmacological inhibition of ILK using a specific ILK inhibitor, QLT0267 potently inhibits YAP-dependent tumor growth in xenograft models 85. The FAK inhibitors PF-562271 and PF-573228 have also been shown to enhance the LATS-mediated inhibitory phosphorylation of YAP 63, 75. A multi-kinase inhibitor CT-707 that predominantly inhibits FAK, anaplastic lymphoma kinase (ALK) and PYK2 is able to render cancer cells vulnerable to hypoxia through YAP inhibition 86. Inhibiting PYK2 activity using the dual PYK2/FAK inhibitor PF431396 destabilizes TAZ and also inhibits YAP/TAZ activity in triple negative breast cancer cells 87.

The SFK member Src prevents the activation of LATS 75, 88, thereby relieves YAP/TAZ inhibition by LATS. Interestingly, SFKs, Src and YES are also shown to activate YAP through direct tyrosine phosphorylation 51-53. Treating cells with SFK inhibitors, such as Dasatinib, PP2, SU6656, AZD0530 and SKI-1 inactivates YAP 51-53, 75, 88. In -catenin-driven cancers, YES facilitates the formation of a tripartite complex comprising -catenin, YAP and TBX5 that drives cell survival and tumor growth 53, 89. The SFK inhibitor dasatinib also serves as YAP inhibitor in these cancers 53. Dasatinib, in addition to inhibiting SFKs may also potently inhibit PDGFR and Ephrin receptors, both of which are known to activate YAP/TAZ 90, 91. However, FAK and SFK inhibitors have shown very limited efficacy against solid tumors in clinical trials therefore their utility in YAP-driven cancers remains to be seen.

MEK (MAP kinase kinase) and YAP interact with each other and maintain transformed phenotypes in liver cancer cells 57. MEK inhibitors PD98059, U0126 and trametinib or MAPK inhibitors CAY10561 and {"type":"entrez-nucleotide","attrs":{"text":"FR180204","term_id":"258307209","term_text":"FR180204"}}FR180204 are able to trigger degradation of YAP in a Hippo-independent manner 57, 58. The finding that MEK inhibition causes YAP degradation is, however, difficult to reconcile if YAP and TAZ are shown to mediate resistance to the MEK inhibitor trametinib 92. The efficacy of trametinib is also being evaluated in EHE, a cancer that is caused by the TAZ-CAMTA1 fusion gene ({"type":"clinical-trial","attrs":{"text":"NCT03148275","term_id":"NCT03148275"}}NCT03148275).

PI3K inhibitors Wortmannin/LY294002 as well as the drug BX795, an inhibitor of its effector 3'-phosphoinositide-dependent kinase-1 (PDK1) prevents nuclear entry of YAP 68. PI3K is closely linked to the mammalian target of rapamycin (mTOR) pathway. mTOR inhibitors temsirolimus and MLN0128 have been shown to inhibit YAP activity in patients with idiopathic pulmonary fibrosis and in a mouse model of cholangiocarcinoma, respectively 93, 94. YAP levels in TSC1 mutant mouse could also be reduced by blocking mTOR using torin1 treatment that induces the autophagy-lysosomal pathway 95.

YAP/TAZ inhibition is an additional unexpected activity possessed by the few kinase inhibitors mentioned above. However, apart from YAP/TAZ inhibition, all other signaling events initiated by the target kinase are also shut down due to inhibitor treatment. If these signaling events are critical for cellular homeostasis, then, toxic side effects will outweigh clinical benefits and this cannot be uncoupled from YAP/TAZ inhibition. Therefore, kinase inhibitors that failed in the trials due to unacceptable toxcity or poor pharmacokinetics may not be repurposed as YAP/TAZ inhibitors in the clinic. Focus should be on the kinase inhibitors that are already in the clinic like EGFR, VEGFR, MEK, PI3K or mTOR inhibitors but efficacy needs to be proven in order to repurpose them as YAP/TAZ inhibitors. The kinase targeted by the inhibitor must activate YAP/TAZ in tumors, for the treatment to be efficacious and this restricts the use of kinase inhibitors to selective tumor types. Intriguingly, YAP/TAZ activation has emerged as a prominent survival strategy adapted by cancers that cause drug resistance to EGFR and its downstream MEK/MAPK inhibitors 31. In such scenarios, coupling a group II YAP/TAZ inhibitor with a EGFR pathway inhibitor might offer the intended treatment benefits.

The mevalonate pathway is essential for the biosynthesis of isoprenoids, cholesterol and steroid hormones. Statins as well as other mevalonate pathway inhibitors like zoledronic acid and GGTI-298 that target farnesyl pyrophosphate synthase and geranylgeranyltransferase, respectively are identified as drugs that restrict the nuclear entry of YAP and TAZ 96, 97. Studies have also shown that combining statins like simvastatin with the EGFR inhibitor gefitinib provides stronger anti-neoplastic effects 98. Atorvastatin and zoledronic acid have entered Phase II clinical trials in triple negative breast cancer to test if they improve the pathological complete response rates ({"type":"clinical-trial","attrs":{"text":"NCT03358017","term_id":"NCT03358017"}}NCT03358017).

Actin polymerization promotes YAP/TAZ nuclear localization and therefore, polymerization inhibitors like latrunculin A 27 and cytochalasin D 28, 29 inhibit YAP/TAZ. Myosin or myosin light-chain kinase inhibitors like blebbistatin and ML-7, respectively have a similar effect 27, 29. Interfering with the actomyosin cytoskeleton through other means, such as Rho inhibition (toxin C3 treatment), or by using Rho kinase inhibitors like Y27632 has also been shown to have an inhibitory effect on YAP/TAZ 27, 29. p21 activated kinase (PAK) family kinases are cytoskeletal regulators as well as Hippo inhibitors. The PAK allosteric inhibitor IPA3 prevents YAP's nuclear entry 63, 99, further, the PAK4 inhibitor PF-03758309 is also shown to reduce YAP levels 77.

YAP/TAZ inhibitory phosphorylation is dynamic and the protein phosphatases PP1 and PP2A are shown to associate with YAP/TAZ and aid in their dephosphorylation and activation. Inhibiting these phosphatases using okadaic acid or calyculin A increases YAP/TAZ phosphorylation and shifts YAP/TAZ to the cytoplasm 54-56. Some of the oncogenic functions of YAP/TAZ are also mediated by the protein-tyrosine phosphatase SHP2 100, therefore SHP2 inhibitors have also been shown to attenuate YAP/TAZ activity 101.

Cellular energy stress is closely linked with attenuation of YAP/TAZ activities 32. Drugs that enhance energy stress like the mitochondrial complex I inhibitors metformin and phenformin, enhance YAP/TAZ inhibitory phosphorylation, cytoplasmic localization and suppression of YAP/TAZ- mediated transcription 32. The energy stress induced by these drugs activates AMPK, which is shown to phosphorylate and stabilize AMOTL1 - a YAP/TAZ negative regulator 32. AMPK is also shown to directly phosphorylate and inactivate YAP by disrupting its interaction with TEADs 33, 34. Therefore, AMPK activators A769662 and AICAR (an AMP-mimetic) are YAP inhibitors 32-34.

Histone deacetylases (HDACs) are uniquely positioned to alter the transcription of target genes. Interestingly, HDAC inhibitors panobinostat, quisinostat, dacinostat, vorinostat and Trichostatin A transcriptionally repress the expression of YAP but not TAZ, and thereby reduce YAP-addicted tumorigenicity 60. Treatment of cholangiocarinoma cells with the HDAC inhibitor {"type":"entrez-nucleotide","attrs":{"text":"CG200745","term_id":"34091806","term_text":"CG200745"}}CG200745 is also shown to decrease YAP levels 102. Although HDAC inhibitors are used to treat hematological malignancies their efficacy in solid cancers is questionable, however, combining HDAC inhibitor panobinostat with BET (bromodomain and extra-terminal) inhibitor I-BET151 achieves more effective YAP inhibition 103. There is also a clinical trial designed to evaluate the efficacy of HDAC/BET inhibitor combination in solid tumors and determination of YAP expression level after drug treatment is used as one of the objectives ({"type":"clinical-trial","attrs":{"text":"NCT03925428","term_id":"NCT03925428"}}NCT03925428). The BET family protein BRD4 is a part of the YAP/TAZ-TEAD transcriptional complex and inhibiting BRD4 using BET inhibitor JQ1 inhibits YAP upregulation and YAP-mediated transcription in KRAS mutant cells 104.

Many group I drugs can potentially be repurposed to treat YAP/TAZ- driven cancers 105. Among the group I drugs, only statins, trametinib and HDAC/BET inhibitors are being evaluated in clinical trials to test if they act against YAP/TAZ. Our prediction is that group I drugs that facilitate YAP/ TAZ inhibitory phosphorylation as well as degradation will have greater success in combating YAP/TAZ in cancers as YAP/TAZ degradation prevents their reactivation through other mechanisms. Importantly, the repurposing of group I drugs would also allow YAP/TAZ and its target gene(s) expression-based stratification amongst cancer patients.

Modalities that target either the TEAD family of transcription factors or YAP/TAZ are classified under this group (Figure ). The majority of the modalities, with the exception of verteporfin 106, target TEADs and are therefore predicted to act in the nucleus. By pairing with the TEAD family of transcription factors, YAP and TAZ upregulate the expression of many oncoproteins. The C-terminus of all TEADs possesses the YAP/TAZ-binding domain. The partnership between YAP/TAZ and TEAD is essential for the initiation of transcriptional program to drive oncogenesis. YAP is no longer oncogenic when sequestered by a dominant negative TEAD that lacks the DNA-binding domain 106. Similarly, a naturally occurring DNA-binding deficient TEAD isoform is also able to inhibit YAP/TAZ-mediated oncogenicity 107. Therefore, directly inhibiting TEAD or preventing YAP/TAZ-TEAD interaction is a promising and most direct strategy that warrants special attention 108.

Disruptors, stabilizers and destabilizers/degraders. A preformed YAP/TAZ-TEAD complex prevents access to drugs that occupy either the TEADs' surface or the palmitate-binding pocket (PBP), however, unassembled TEADs are accessible to drugs. Majority of the known YAP/TEAD-binding compounds are disruptors as they prevent the formation of the YAP/TAZ-TEAD complex. Two other classes of TEAD-binding compounds are stabilizers and destabilizers/degraders. Stabilizers either stabilize TEAD expression levels or enhance the formation of the YAP/TAZ-TEAD complex. Destabilizers bind to TEADs' surface or PBP and reduce TEAD expression levels through in situ denaturation, degraders on the other hand direct TEADs for proteasomal degradation.

Group I drugs target the upstream YAP/TAZ-activating proteins like the EGFR, GPCR, Src, or Integrins. As there are so many upstream YAP/TAZ activators, group I drugs are vulnerable to oncogenic bypass where inhibition of one group I YAP/TAZ activator leads to selection of cancer cells that activate YAP/TAZ via another group I activator. Strategically, Group II drugs may address this issue by directly targeting YAP/TAZ or TEAD, the converging points for various pathways and also the effectors for oncogenic transcription. However, Group II targeting modalities are still at the exploratory stage and it remains to be seen whether it is feasible to develop a Group II modality that works in clinic. We also need to be mindful of the possible associated toxicities due to YAP/TAZ-TEAD inhibition 109.

Most of the reported Group II modalities are disruptors; they target YAP/TAZ or TEAD and prevent their binary interaction. However, in addition to disruptors, in the future, we predict the emergence two other classes of group II compounds that would act as TEAD stabilizers and destabilizers/degraders (Figure ).

A small molecule benzoporphyrin drug named Verteporfin (VP) was shown to have the ability to bind to YAP and disrupt the YAP-TEAD interaction 106. VP is also able to inhibit YAP-induced excessive cell proliferation in YAP- inducible transgenic mice and in NF2 (upstream Hippo pathway component) liver-specific knockout mouse models 106. Although we do not understand the molecular details of VP binding to YAP, it is still undoubtedly the most popular YAP inhibitor within the scientific community. However, we need to be cautious as some of the tumor-inhibitory effects of VP are reported to be YAP- independent 110, 111. VP is photosensitive and proteotoxic and there is a need for better derivatives. A VP derivative, a symmetric divinyldipyrrine was shown to inhibit YAP/TAZ-dependent transcription but it is not clear if the compound specifically binds to YAP 112.

YAP and TAZ bind on the TEADs' surface; Inventiva Pharma has identified several compounds with benzisothiazole-dioxide scaffold that bind to the TEADs' surface and disrupt the YAP/TAZ-TEAD interaction. These compounds are currently in the lead optimization stage and have the potential to treat malignant pleural mesothelioma as well as lung and breast cancers that are driven by YAP/TAZ 113.

YAP cyclic peptide (peptide 17) and cystine-dense peptide (TB1G1) are also disruptors of YAP/TAZ-TEAD interaction in vitro but they have poor cell-penetrating abilities 114, 115. Interestingly, a peptide derived from the co-regulator Vgll4 appears to have remarkable cell-penetrating abilities and inhibits YAP-mediated tumorigenesis in animal models 116. Vgll proteins, named Vgll1-4 in mammals, belong to another class of co-regulators that pair with TEADs in a structurally similar, and therefore, in a mutually exclusive manner with YAP and TAZ 117, 118.

We identified a novel druggable pocket in the center of the TEADs' YAP/TAZ- binding domain 119 that could be occupied by fenamate drugs. Palmitate was subsequently shown to occupy this pocket, hereafter referred to as the palmitate-binding pocket (PBP). TEAD palmitoylation is shown to be important for stability and for the interaction with YAP 120, 121. Although the fenamate drug flufenamic acid competes with palmitate for binding to TEAD, higher concentrations are needed for it to be effective and it is not a disruptor of the interaction between YAP/TAZ with TEADs 122. However, covalently linking the fenamate to TEAD, using a chloromethyl ketone substitution, enables it to disrupt the YAP-TEAD interaction 123. The non-fused tricyclic compounds identified by Vivace Therapeutics could also be considered as fenamate analogs but it remains to be seen if they function as disruptors 124. Through structure-based virtual screen, vinylsulfonamide derivatives were identified as compounds that bind to PBP 125. Optimization of these derivatives yielded DC-TEADin02 a covalent TEAD autopalmitoylation inhibitor with an IC50 value of 200 nM. Interestingly, DC-TEADin02 is able to inhibit TEAD activity without disrupting the YAP-TEAD interaction.

Palmitate, by occupying the PBP, allosterically modulates YAP's interaction with TEAD 121, therefore it is conceivable that there might be small molecules that occupy the PBP and allosterically disrupt YAP/TAZ's interaction with TEADs. To this end, Xu Wu's group has identified and patented several potent compounds with alkylthio-triazole scaffold as PBP- occupying compounds that prevent YAP-TEAD interaction in cells 126. Another potent TEAD inhibitor that occupies the PBP is the small molecule K-975 127. K-975 also disrupts the YAP-TAZ-TEAD interaction and displayed anti-tumorigenic properties in malignant pleural mesothelioma cell lines much akin to the loss of YAP. Although palmitate is covalently attached to TEAD, it is a reversible modification and addition of PBP-occupying small molecules reduce the cellular palmitoylation status of TEADs 126. Moreover, the palmitoyl group is also removed from TEADs by depalmitoylases 128.

Being predominantly unstructured, YAP and TAZ are difficult to target directly. However, TEADs offer two attractive ways for targeting, one is to directly block the YAP/TAZ-binding pocket on the TEADs' surface with small molecules or peptides, whilst the other is to leverage on the PBP and allosterically disrupt YAP/TAZ interaction or inhibit TEADs (Figure ). However, the molecular determinants that confer YAP/TAZ disrupting ability to PBP-occupying small molecules are not clear. We do not know why flufenamate and DC-TEADin02 are unable to disrupt YAP/TAZ-TEAD interaction, like chloromethyl fenamate, K-975 and compounds with alkylthio-triazole scaffold.

The PBP could also be leveraged to allosterically enhance YAP/TAZ-TEAD stability or interaction. This prediction is subject to the identification of small molecules that functionally mimic the ligand palmitate (Figure ). Compounds with such an ability will enhance TEAD-dependent transcription and may have therapeutic value for regenerative medicine where enhancement of YAP/TAZ- TEAD activity is needed to repair damaged tissues 129. We recently identified that quinolinols occupy the PBP, stabilize YAP/TAZ levels and upregulate TEAD-dependent transcription 130. Enhanced YAP/TAZ levels increase the pool of assembled YAP/TAZ complex and therefore quinolinols could be considered as stabilizers (Figure ).

We identified a few chemical scaffolds that have the ability to occupy the PBP and destabilize TEAD (unpublished results). Addition of these compounds unfolds the TEADs' YAP/TAZ-binding domain and we call these compounds destabilizers (Figure ). Degraders could be generated when potent and selective TEAD surface or PBP-occupying compounds are coupled to proteolysis targeting chimera (PROTAC) 131 to direct TEAD proteasomal degradation. Therefore, destabilizers aim to reduce the cellular concentration of TEADs through in situ unfolding and degraders reduce TEAD levels through proteasomal degradation. Reducing the levels of their interacting partners deprives YAP/TAZ of their ability to activate transcription.

Any TEAD-binding compounds (disruptors, stabilizers or destabilizers/degraders) can only access unbound TEADs, as binding of YAP and TAZ blocks both the surface and the palmitate-binding pockets (Figure ). After accessing unbound TEADs, the disruptors and destabilizers/degraders reduce, whereas the stabilizers enhance, the formation of the YAP/TAZ-TEAD complex.

YAP/TAZ-mediated tumor development is due to the collective action of the repertoire of proteins that are expressed under their influence. However, some proteins are able to drive oncogenesis much better than others and they vary depending on the solid tumor and context. Therefore, drugs against these downstream YAP/TAZ targets including metabolic enzymes, kinases, ligands and proteins, such as BCL-xL, FOXM1 and TG2 are also used to combat YAP/TAZ-mediated oncogenicity (Figure ).

TAZ-dependent expression of ALDH1A1 (aldehyde dehydrogenase) is shown to impart stemness and tumorigenic ability; inhibition of ALDH1A1 using A37 reverses this transformation 132. GOT1 - the aspartate transaminase induced by YAP/TAZ, confers glutamine dependency to breast cancer cells and targeting this metabolic vulnerability using aminooxyacetate (AOA) represses breast cancer cell proliferation 133. Targeting the YAP/TAZ transcriptional target cyclooxygenase 2 (COX-2) using celecoxib inhibits cell proliferation and tumorigenesis in NF2 mutant cells 134. Interestingly, a positive feedback is seen in hepatocellular carcinoma cell lines where COX-2 is also shown to increase the expression of YAP 135. Inhibiting COX-2 using NS398 stimulates LATS-dependent phosphorylation of TAZ 136.

In hepatocellular carcinoma, Axl kinase has been shown to be crucial for mediating several YAP-driven oncogenic functions like cell proliferation and invasion 137. Similarly, YAP-driven Axl expression has been implicated in the development of resistance against EGFR inhibitors in lung cancer and sensitivity could be restored through Axl inhibition using TP-0903 138. YAP is shown to upregulate the expression of the kinase NUAK2 139 that, in turn activates YAP/TAZ by inhibiting LATS. Specific pharmacological inhibition of NUAK2 using WZ400 shifts YAP/TAZ to the cytoplasm and reduces cancer cell proliferation 140.

In a mouse model of prostate adenocarcinoma, the YAP-TEAD complex promotes the expression of the chemokine ligand CXCL5 that facilitates myeloid-derived suppressor cells (MDSC) infiltration and adenocarcinoma progression. Administering CXCL5 neutralizing antibody, or blocking CXCL5 receptor using the inhibitor SB255002, inhibits MDSC migration and tumor burden 40. The notch ligand Jagged-1 that is upregulated by YAP/TAZ is crucial for liver tumorigenesis 59, 141. Treating liver tumor cells with Jagged-1 neutralizing antibody greatly reduces oncogenic traits. The levels of integrin ligands CTGF and CYR61 that are also YAP target genes, could be reduced using the cyclopeptide RA-V (deoxybouvardin) leading to a reduction of YAP- mediated tumorigenesis in mst1/2 (Hippo homolog) knockout mouse model 142. Although neutralizing CTGF (FG-3019/pamrevlumab) and CYR61 (093G9) antibodies are available, they have not been effectively used against YAP/TAZ-driven cancers.

YAP mediates drug resistance to RAF- and MEK-targeted therapies in BRAF V600E cells, in part through the expression of the anti-apoptotic protein BCL- xL. BCL-xL inhibition using navitoclax sensitizes these cells to targeted therapies 92.

YAP-mediated proliferation through its target gene FOXM1 could be prevented in sarcoma cell lines and mouse models through the administration of thiostrepton that reduces FOXM1 levels 143.

Transglutaminase 2 (TG2) - the multifunctional transamidase is a YAP/TAZ target gene that is important for cancer stem cell survival and for maintaining integrin expression. TG2 inhibition using NC9 dramatically reduces tumorigenicity 144, 145.

We are aware that many of these target proteins also act upstream and stimulate YAP/TAZ by forming a positive feedback but we would nevertheless consider them in this group and not as group I as their expression is influenced by the TEAD-binding motif and YAP/TAZ.

Although attractive, toxicity issues and the identification of responsive patient population could be challenges in the successful implementation of the YAP/TAZ inhibitors in the clinic. YAP/TAZ inhibition might elicit toxicity 146; homozygous disruption of YAP in mice causes embryonic lethality, whereas TAZ knockouts are viable 147-150. Tissue-specific deletions of YAP in the heart 151, lung 152 or kidney 153 cause hypoplasia, whereas YAP/TAZ deletion in the liver cause hepatomegaly and liver injury 154. Surprisingly, YAP/TAZ knockouts in the intestine are well tolerated with no apparent tissue defects 155. All of these suggest that YAP and TAZ are crucial for development. However, they appear to be dispensable for adult tissue homeostasis. In most adult tissues, under normal homeostasis, YAP/TAZ are found restricted to the cytoplasm and are activated primarily in response to injury to initiate tissue regeneration. Therefore, it is predictable that administration of a YAP/TAZ inhibitor may not elicit severe toxicity. However, given the dynamic shuttling of YAP/TAZ/Yorkie between nucleus and cytoplasm 156-158, it is feasible that they still have a role in normal tissue homeostasis. Fittingly, YAP has been identified to be important for podocyte homeostasis and its functional inactivation compromises the glomerular filtration barrier and cause renal disease 109. Along similar lines, renal toxicity was observed in mice administered with K-975 - a YAP/TAZ-TEAD inhibitor 127. Renal toxicity in targeted therapy is very common and is seen in most of the kinase inhibitors used in oncology 159. Yet these kinase inhibitors are in the clinic as there is a therapeutic window, where the drug could be dosed to improve patient survival without causing much toxicity. The same could be envisaged for YAP/TAZ-inhibiting drugs.

Several drugs that act as YAP/TAZ inhibitors target multiple signaling pathways. Targeting multiple pathways could be a boon or a bane. Drug resistance is minimized in a multi-targeted approach as potential bypass mechanisms are also targeted. However, toxicity becomes an issue when the drug targets multiple important signaling pathways. For instance, raising cAMP through the use of PDE inhibitors activates a multitude of proteins like PKA, EPACs, ion channels and small GTPases. Similarly, GPCR modulators influence multiple pathways through signaling via G proteins, arrestins or GPCR kinases. To reduce toxic side effects, there are options available like selective targeting or biased signaling. Instead of hitting all the PDEs, the PDE enzyme that is the most potent activator of YAP/TAZ should be selectively targeted. Nonspecific PDE inhibitors cause more severe side effects than sub-type selective PDE inhibitors 160. Similarly, through stabilizing a particular GPCR conformation, certain small molecule GPCR modulators are able to effect signaling bias where one GPCR effector is preferentially activated over others, say G proteins over -arrestins, this way only a subset of signaling pathways get activated 161.

Another major challenge is the identification of patients responding to a YAP/TAZ inhibitor. YAP/TAZ expression is low in normal tissues and their levels are significantly elevated in cancers. Is YAP or TAZ positivity in tumors sufficient criteria to administer a YAP/TAZ inhibitor? YAP and TAZ might not be transcriptionally active or drivers in all tumors. Further, they could be expressing target genes that negatively regulate their activity 162, 163. There are also tumor types where YAP/TAZ or TEAD levels have no prognostic significance 46. These YAP/TAZ positive tumors are unlikely to respond to a YAP/TAZ inhibitor. Barring a few such scenarios, in many solid tumors, YAP or TAZ expression levels correlate well with higher-grade cancers or poor prognosis. Tumors with nuclear YAP or TAZ that are also positive for the downstream oncogenic YAP/TAZ target genes are likely to respond to a YAP/TAZ inhibitor and this should be used as criteria for patient stratification. As many of the YAP/TAZ-TEAD target genes are secreted proteins, the expression levels of these in the serum could also be estimated in addition to assessing their levels through immunohistochemistry.

As YAP and TAZ contribute to the acquisition of many hallmarks of cancer traits, targeting them is predicted to be more relevant for the management of several cancer types. It is still early to expect a newly developed drug against YAP/TAZ but it is nevertheless disconcerting to see that there are hardly any clinical trials that evaluate if known drugs could be repurposed as YAP/TAZ- inhibitors. Group I drugs are well suited to repurpose 105 but only statins ({"type":"clinical-trial","attrs":{"text":"NCT03358017","term_id":"NCT03358017"}}NCT03358017); trametinib ({"type":"clinical-trial","attrs":{"text":"NCT03148275","term_id":"NCT03148275"}}NCT03148275) and epigenetic modulators ({"type":"clinical-trial","attrs":{"text":"NCT03925428","term_id":"NCT03925428"}}NCT03925428) are being evaluated in clinical trials, assessment of the expression levels of YAP/TAZ after drug treatment is used as one of the clinical trial objectives. It is essential that we bolster our pharmacological arsenal so that we are prepared to combat YAP and TAZ. Group I drugs that failed in oncology trials are not expected to fare any better against YAP/TAZ. However, drugs that are already in the clinic like the kinase inhibitors targeting the EGFR or MEK, PDE inhibitors as well as GPCR modulators could be repurposed to combat YAP/TAZ. The cancer types need to be carefully stratified to ensure they are driven by YAP/TAZ through the upstream stimulator targeted by the drug. To overcome potential bypass mechanism or drug resistance, combinatory use of group I and II drugs could also serve as an avenue for cancer treatment. For the group III drugs, the situation may not be as promising, as they target only one of the many possible oncogenic proteins regulated by YAP/TAZ. Again, combinatory inhibition of few downstream target genes could be considered if they are collectively essential for oncogenic manifestation of YAP/TAZ-driven transcription. As they are new and untested, there is much excitement and progress in the development of novel group II compounds as drugs against YAP/TAZ. We are at an exciting juncture in the Hippo field where we could potentially see a novel group II drug or a repurposed group I drug to combat YAP/TAZ in the near future.

A.V. Pobbati and W. Hong are supported by the Agency for Science, Technology, and Research (A*STAR), Singapore. We thank Sayan Chakraborty, Gandhi T.K.B. and John Hellicar for critical reading of this review. We apologize to all authors whose work was not cited due to space constraints.

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A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy

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Disease in a dish: What mini-hearts and other organs reveal about long COVID - telegraphherald.com

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Chemotherapy is a standard treatment for many different types of cancer.

Chemicals in chemotherapy drugs stop cancer cells from growing and spreading. These chemicals can also damage healthy cells, especially ones that divide quickly. This includes cells in your skin, digestive tracts, and bone marrow.

Damage to these cells can cause side effects. One common side effect is chemotherapy-induced anemia.

Anemia means you dont have enough red blood cells to properly carry oxygen around your body. This condition develops when chemotherapy drugs damage the cells in your bone marrow that create red blood cells.

Anemia usually goes away once chemotherapy stops but can lead to potentially serious complications when it develops. In this article, we break down causes of chemotherapy-induced anemia, signs and symptoms, and potential complications.

More than 100 types of medications have been developed to treat cancer, according to the University of Iowa Hospitals and Clinics. Different medications disrupt cancer growth in different ways, and all have potential side effects.

The chemicals in chemotherapy drugs mainly target cells that replicate quickly. Along with cancer cells, these drugs can damage healthy cells. A low red blood cell count caused by these medications is called chemotherapy-induced anemia.

The erythroid progenitor cell is particularly vulnerable to chemotherapy, according to 2018 research. These cells are found in your bone marrow and become red blood cells. If many of these cells are damaged, you can develop a low red blood cell count.

A low red blood cell count means your blood has less hemoglobin than average. Hemoglobin is the protein in red blood cells that carries oxygen to all your bodily tissues.

Its estimated that 70 percent of people who receive chemotherapy develop anemia. Its most common in people with:

At least 50 to 60 percent of people with these cancers require at least one blood transfusion. A transfusion is a procedure where youre given donated blood through an IV.

Chemotherapy-induced anemia is also common in people with low hemoglobin levels prior to treatment and people receiving platinum-based chemotherapy medications, according to the American Cancer Society. These medications include:

According to 2019 research, signs and symptoms of chemotherapy-induced anemia can overlap with cancer symptoms. These symptoms often include:

Other signs and symptoms may include:

Research from 2020 suggests anemia can negatively affect the survival rate of people receiving treatment for cancer. Severe anemia may delay or reduce part of your chemotherapy treatment, which can lead to worsened results.

Treatment for anemia may include:

A blood transfusion involves receiving blood from a donor through an IV. Donated blood needs to match your blood type or your immune system may attack the foreign blood cells. Transfusions can help quickly reduce your symptoms by increasing the circulation of oxygen to your organs and tissues.

Transfusions are commonly performed when hemoglobin levels drop below 8.0 grams per deciliter (g/dL) of blood.

A medical professional can administer erythropoietin-stimulating agents as a shot under your skin. Theyre synthetic versions of the hormone erythropoietin produced by your kidneys. This hormone stimulates the production of red blood cells.

It usually takes 4 to 6 weeks for these drugs to have a significant effect, and about a third of people dont respond at all. Healthcare professionals usually only recommend them for people receiving palliative treatment to ease symptoms of anemia when cancer isnt considered curable, according to 2019 research.

Erythropoietin-stimulating agents can help increase your hemoglobin levels and reduce the need for blood transfusions, but theyre associated with serious health complications and an increased risk of death, according to 2009 research.

About 65 percent of your bodys iron is found in hemoglobin, a protein in your blood that carries oxygen to your bodys organs and tissues. Without enough iron, blood cells cant carry oxygen to cells throughout your body. Low iron levels can also lead to anemia.

Your doctor may give you a prescription for an iron supplement or tell you to eat more high iron foods, like:

Researchers are still investigating the potential benefits of iron supplementation for people receiving erythropoietin-stimulating agents. Research from 2017 suggests that it may help reduce the need for blood transfusions.

Your doctor may also give you a prescription for folic acid (vitamin B9) or vitamin B12. These vitamins are also necessary to produce red blood cells.

Chemotherapy-induced anemia often goes away once treatment ends and your body has time to repair itself. According to the Canadian Cancer Society, low blood cell counts typically begin to recover 2 to 4 weeks after chemotherapy ends.

In the meantime, you can do the following to manage your symptoms:

According to the American Cancer Society, anemia has been found to shorten the lifespan of people with cancer. It may delay cancer treatment, and sometimes the lack of oxygen to your cells can be life threatening.

If your tissues arent getting enough oxygen, your heart has to work harder to move blood through your body. According to the National Heart, Lung, and Blood Institute, increased stress on your heart can worsen already present heart problems or lead to conditions such as:

Breathing problems from anemia can make everyday tasks, like walking, difficult and impact your quality of life.

Anemia is a common side effect of chemotherapy. The chemicals in chemotherapy medications that destroy cancer cells can also damage healthy cells in your body. Anemia usually passes once chemotherapy stops.

Your cancer team can help you manage symptoms of anemia through medications, blood transfusions, and prescribing vitamins and minerals. Its important to communicate with your team about any new symptoms you develop so you can build the best treatment plan possible.

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Chemotherapy-induced Anemia: Symptoms, Treatment & More - Healthline

Skin Stem Cells Comments Off on Chemotherapy-induced Anemia: Symptoms, Treatment & More – Healthline | March 22nd, 2022

HuffPosts Small Business Spotlight is a series aimed at highlighting the small businesses that are making a positive difference while forging new and significant futures in commerce.

Your scalp is really just an extension of the skin on your face, so why dont we care for it in the same way? Studies have shown that theres a direct correlation between scalp health and hair health and retention.

Helen Reavey, a hair stylist and trichologist, set out to solve that problem and found a solution in creating Act+Acre, a sustainable hair care line that focuses on improving the condition of the scalp first so that healthy hair can follow.

Throughout her 20-year career in the hair industry, Reavey worked in salons and at fashion weeks across the globe, and began to notice a pattern in the hair she saw and styled. Scalps were red and raw from overstyling and product buildup on the scalp, accompanied by dead and damaged hair.

I said to myself that I wished I had something to send these girls home with to dissolve the product, calm down inflammation and just really deliver nutrients to the scalp, the skin and the hair follicle, Reavey told HuffPost.

Now, products like Act+Acres Scalp Detox and Scalp Renew do just that by breaking down excess sebum, dead skin cells and product buildup, making the way for more abundant and healthier hair growth. Among other treatments, theres also a Stem Cell Serum that nourishes the hair follicle and helps to extend the growth phase.

Reavey said that the connection between scalp health and hair health seemed to be widely overlooked within the beauty industry, noting that caring for the scalp really goes beyond just the immediate improvements you may see once you start to address some of the most common concerns like itching, flaking and lack of hair volume.

Its really about from five to seven years from now that the hair in that cycle will really start to show what you were doing to it five, seven years ago. Its like when we work to prevent lines, wrinkles or sun damage now because we dont want them to appear in another five to 10 years, she said.

For Reavey, the conception and subsequent launch of Act+Acre in 2019 was also about challenging the norms and processes of the larger corporations that came before her their systems of transparency (or lack thereof) with their consumers, their wasteful approach to production and product development, and the kinds of ingredients being used.

Act+Acre uses a cold process method to create all of their products, a patented system that involves a hyperbaric chamber, cold air and pressure to extract the most from ingredients at their highest concentrations, which is possible because they arent evaporated off in the process. It also uses 90% less energy than traditional and cheaper methods with heat.

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This Hair Care Line Gives You Luscious Locks By Improving Your Scalp Health - HuffPost

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