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The ‘supercells’ that cured an infant’s grave genetic illness – Japan Today

By daniellenierenberg

When a person's immune system is impaired by a genetic disease, a bone-marrow transplant can be a powerful therapeutic tool, but with a major downside: during the first few months the recipient's defenses against viruses are severely weakened. The slightest infection can lead to a hospital trip.

A still-experimental type of treatment known as T-cell therapy aims to assist during this vulnerable period -- the months during which the body is rebuilding its natural defenses. After two decades of clinical trials, the technology has been refined, and is being used to treat more and more patients, many of them children.

A boy named Johan is one of them.

Today he is a mischievous, smiling toddler with a thick shock of light-brown hair, who never tires, playfully tormenting the family's puppy, Henry. There is no sign of the three-year-long medical and emotional roller-coaster ride he and his family, who live in an affluent Washington suburb, have been on.

The first traumatic surprise came with the results of a pregnancy test: Johan was not planned.

"That was a huge shock. I cried," said his mother, 39-year-old Maren Chamorro.

She had known since childhood that she carried a gene that can be fatal in a child's first 10 years, chronic granulomatous disease (CGD). Her brother died of it at the age of seven. The inexorable laws of genetics meant that Maren had a one in four chance of transmitting it to her child.

For their first children, she and her husband Ricardo had chosen in-vitro fertilization, allowing the embryos to be genetically tested before implantation.

Their twins Thomas and Joanna were born -- both disease-free -- seven and a half years ago. But in Johan's case, a post-birth genetic test quickly confirmed the worst: he had CGD.

After conferring with experts at Children's National Hospital in Washington, the couple took one of the most important decisions of their lives: Johan would receive a bone-marrow transplant, a risky procedure but one that would give him a chance of a cure.

"Obviously, the fact that Maren had lost a sibling at a young age from the disease played a big role," Ricardo confided.

Bone marrow, the spongy tissue inside bones, serves as the body's "factory" for the production of blood cells -- both red and white.

Johan's white blood cells were incapable of fighting off bacteria and fungal infections. A simple bacterial infection, of negligible concern in a healthy child, could spread out of control in his young body.

Luckily, Johan's brother Thomas, six years old at the time, was a perfect match. In April 2018, doctors first "cleansed" Johan's marrow using chemotherapy. They then took a small amount of marrow from Thomas's hip bones using a long, thin needle.

From that sample they extracted "supercells," as Thomas calls them -- stem cells, which they reinjected into Johan's veins. Those cells would eventually settle in his bone marrow -- and begin producing normal white blood cells.

The second step was preventive cell therapy, under an experimental program led by immunologist Michael Keller at Children's National Hospital.

The part of the immune system that protects against bacteria can be rebuilt in only a matter of weeks; but for viruses, the natural process takes at least three months.

From Thomas's blood, doctors extracted specialized white blood cells -- T-cells -- that had already encountered six viruses.

Keller grew them for 10 days in an incubator, creating an army of hundreds of millions of those specialized T-cells. The result: a fluffy white substance contained in a small glass vial.

Those T-cells were then injected into Johan's veins, immediately conferring protection against the six viruses.

"He has his brother's immune system," said Keller, an assistant professor at Children's National.

Johan's mother confirmed as much: today, when Thomas and Johan catch a cold, they have the same symptoms, and for nearly the same amount of time.

"I think it's pretty cool to have immunity from your big brother," Maren Chamorro said.

This therapeutic approach -- boosting the body's immune system using cells from a donor or one's own genetically modified cells -- is known as immunotherapy.

Its main use so far has been against cancer, but Keller hopes it will soon become available against viruses for patients, like Johan, who suffer from depressed immune systems.

The chief obstacles to that happening are the complexity of the process and the costs, which can run to many thousands of dollars. These factors currently restrict the procedure to some 30 medical centers in the United States.

For Johan, a year and a half after his bone marrow transplant, everything points to a complete success.

"It's neat to see him processing things, and especially play outside in the mud," his mother said. "You know, what a gift!"

Her only concern now is the same as any mother would have -- that when her son does fall ill, others in the family might catch the same bug.

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CohBar Discovers Novel Peptide Inhibitors of CXCR4, a Key Regulator of Tumor Growth and Metastasis – Associated Press

By daniellenierenberg

MENLO PARK, Calif., Jan. 08, 2020 (GLOBE NEWSWIRE) -- CohBar, Inc. (NASDAQ: CWBR), a clinical stage biotechnology company developing mitochondria based therapeutics (MBTs) to treat chronic diseases and extend healthy lifespan, today announced the discovery of a series of novel mitochondrial peptide analogs with potent in vitro activity as selective inhibitors of C-X-C Chemokine Receptor Type 4 (CXCR4) and with preliminary in vivo efficacy in a mouse model of melanoma, including substantial reduction in tumor growth as compared to control animals. CXCR4 is a key regulatory receptor involved in tumor growth, invasion, angiogenesis, metastasis, and resistance to therapy.

This new discovery offers the potential to develop novel therapeutics for difficult-to-treat cancers, based on peptides encoded in the mitochondrial genome, said Ken Cundy, Ph.D., CohBars Chief Scientific Officer. Inhibition of this key regulatory pathway is potentially applicable to a wide range of cancers, as well as orphan indications where CXCR4 signaling is dysregulated.

Novel peptide analogs of a mitochondrially encoded peptide (MBT5) demonstrated potent and selective inhibition of human CXCR4 receptor in cell-based assays, with IC50 values in the low nanomolar concentration range. In a difficult-to-treat in vivo mouse model of melanoma, the B16F10 syngeneic tumor model, the combination of an analog of MBT5 administered subcutaneously with the chemotherapeutic temozolomide showed enhanced antitumor activity, reducing tumor growth after 11 days by 61% compared to control animals. The reduction in tumor growth produced by the combination exceeded the effect of either temozolomide used as a single agent, which reduced tumor growth by 38% compared to control, or the murine checkpoint inhibitor anti-PD-1 antibody, which had no effect on tumor growth in this model.

CohBar plans to further explore the efficacy of this new family of peptides in additional animal models with the goal of identifying a new clinical development MBT candidate.

These new data further expand our understanding of the broad regulatory influence exerted by mitochondria and the therapeutic potential of analogs of peptides encoded in mitochondrial DNA, said Steve Engle, CohBar CEO. We are just beginning to scratch the surface of this previously untapped field.

CXCR4 is overexpressed in more than 75% of cancers and high levels of the receptor are associated with poor survival prognosis. Inhibition of the CXCR4 receptor has been shown to mobilize immune cells, enhance the effects of chemotherapy and immunotherapy in various cancers, and reduce the development of metastatic tumors by blocking the ability of tumor cells to evade immune surveillance. CXCR4 also regulates the homing and retention of hematopoietic stem cells and malignant cells in the bone marrow.

Further details of these new studies will be available on the CohBar website at http://www.cohbar.com.

About CohBar

CohBar (NASDAQ: CWBR) is a clinical stage biotechnology company focused on the research and development of mitochondria based therapeutics, an emerging class of drugs for the treatment of chronic and age-related diseases. Mitochondria based therapeutics originate from the discovery by CohBars founders of a novel group of naturally occurring mitochondrial-derived peptides within the mitochondrial genome that regulate metabolism and cell death, and whose biological activity declines with age. To date, the company has discovered more than 100 mitochondrial-derived peptides. CohBars efforts focus on the development of these peptides into therapeutics that offer the potential to address a broad range of diseases, including nonalcoholic steatohepatitis (NASH), obesity, fibrotic diseases, cancer, type 2 diabetes, and cardiovascular and neurodegenerative diseases. The companys lead compound, CB4211, is in the phase 1b stage of a phase 1a/1b clinical trial that includes an evaluation of biological activity relevant to NASH and obesity.

For additional company information, please visit http://www.cohbar.com.

Forward-Looking Statements

This news release contains forward-looking statements which are not historical facts within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are based only on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and other future conditions. In some cases you can identify these statements by forward-looking words such as believe, may, will, estimate, continue, anticipate, intend, could, should, would, project, plan, expect, goal, seek, future, likely or the negative or plural of these words or similar expressions. Examples of such forward-looking statements including but not limited to statements regarding the ability of mitochondrial peptide analogs to reduce tumor growth in mice; anticipated outcomes of research and clinical trials for our mitochondria based therapeutic (MBT) candidates; expectations regarding the growth of MBTs as a significant future class of drug products; and statements regarding anticipated therapeutic properties and potential of our mitochondrial peptide analogs and MBTs. You are cautioned that such statements are not guarantees of future performance and that actual results or developments may differ materially from those set forth in these forward looking statements. Factors that could cause actual results to differ materially from these forward-looking statements include: our ability to successfully advance drug discovery and development programs, including the delay or termination of ongoing clinical trials; our possible inability to mitigate the prevalence and/or persistence of the injection site reactions, receipt of unfavorable feedback from regulators regarding the safety or tolerability of CB4211 or the possibility of other developments affecting the viability of CB4211 as a clinical candidate or its commercial potential; results that are different from earlier data results including less favorable than and that may not support further clinical development; our ability to raise additional capital when necessary to continue our operations; our ability to recruit and retain key management and scientific personnel; and our ability to establish and maintain partnerships with corporate and industry partners. Additional assumptions, risks and uncertainties are described in detail in our registration statements, reports and other filings with the Securities and Exchange Commission and applicable Canadian securities regulators, which are available on our website, and at http://www.sec.gov or http://www.sedar.com.

You are cautioned that such statements are not guarantees of future performance and that our actual results may differ materially from those set forth in the forward-looking statements. The forward-looking statements and other information contained in this news release are made as of the date hereof and CohBar does not undertake any obligation to update publicly or revise any forward-looking statements or information, whether as a result of new information, future events or otherwise, unless so required by applicable securities laws. Nothing herein shall constitute an offer to sell or the solicitation of an offer to buy any securities.

Investor and Media Contact:Jordyn TaraziDirector of Investor RelationsCohBar, Inc.(650) 445-4441 Jordyn.tarazi@cohbar.com

Joyce AllaireLifeSci Advisors, LLC jallaire@lifesciadvisors.com

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New Treatment Approved in Canada for Most Common Type of Leukemia – Canada NewsWire

By daniellenierenberg

CALQUENCE (acalabrutinib) is now available for adult patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia

MISSISSAUGA, ON, Jan. 8, 2020 /CNW/ - AstraZeneca Canada today announced that Health Canada has approved Calquence (acalabrutinib), an oral Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of adult patients with chronic lymphocytic leukemia (CLL), as monotherapy or in combination with obinutuzumab in the first-line setting, and as monotherapy for relapsed/refractory (r/r) disease.1

CLL is the most common type of leukemia in adults, accounting for 44 per cent of all cases in Canada.2 Morethan 2,200 people in Canada are diagnosed with the disease each year and more than 600 will die from it.3,4 Despite advancements in the treatment of CLL, there is still no cure for the disease and even after successful initial treatment, some patients may relapse, leaving them in need of further innovation.

"CLL is most often diagnosed when patients are more than 60 years old, at a time when they are already dealing with other health conditions related to aging and are trying to maintain the best quality of life," says Antonella Rizza, CEO of Lymphoma Canada. "Today's announcement offers Canadians living with CLL an important new option for this incurable but treatable disease."'

The Canadian approval was granted under Project Orbis, a new international health authority collaboration which provides a framework for simultaneous submission and review of oncology products among international partners.5Under this collaboration, Health Canada, the U.S. FDA, and the Australian Therapeutic Goods Administration (TGA) collectively reviewed the application for Calquence, making it the second treatment approved as part of the program and the first in hematology.

"In the last several years, we've been moving away from traditional chemotherapies to more targeted therapies for CLL." said Dr. Carolyn Owen, Alberta Health Services, Calgary. "Health Canada's approval of acalabrutinib provides a new effective and well tolerated treatment option for CLL patients and improves their treatment options."

The Health Canada approval of Calquence was based on positive interim data from two Phase III clinical trials, ELEVATE-TN and ASCEND.6,7The ELEVATE-TN trial evaluated the safety and efficacy of Calquence in combination with obinutuzumab, a CD20 monoclonal antibody, or Calquence alone versus chlorambucil, a chemotherapy, in combination with obinutuzumab in previously untreated patients with CLL. The ASCEND trial evaluated the efficacy of Calquence in previously treated patients with CLL.Together, the trials showed that Calquence in combination with obinutuzumab or as a monotherapy significantly reduced the relative risk of disease progression or death. Across both trials, the safety and tolerability of Calquence were consistent with its established profile.1

About chronic lymphocytic leukemia (CLL)Chronic lymphocytic leukemia is the most common type of leukemia in adults, which begins in the bone marrow, and progresses slowly.8 In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections.9 As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells and platelets.9This could result in anaemia, infection and bleeding.9B-cell receptor signalling through BTK is one of the essential growth pathways for CLL. Many people with CLL do not have any symptoms upon diagnosis, and the disease is often found in blood tests for unrelated health problems.10

AboutCalquenceCalquence(acalabrutinib; previously known as ACP-196) is a selective inhibitor of Bruton's tyrosine kinase (BTK).1Calquencebinds covalently to BTK, thereby inhibiting its activity, and has demonstrated this with minimal interactions with other immune cells in pre-clinical studies.1,6,7In B cells, BTK signaling results in activation of pathways necessary for B cell proliferation, trafficking, chemotaxis and adhesion.1 The recommended dose ofCalquenceis one 100mg capsule taken orally twice daily (approximately 12 hours apart), until disease progression or unacceptable toxicity.1Calquencemay be taken with or without food.1

About AstraZenecaAstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of primary and specialty care medicines that transform lives. Our primary focus is on three important areas of healthcare: Cardiovascular and Metabolic disease; Oncology; and Respiratory, Inflammation and Autoimmunity. AstraZeneca operates in more than 100 countries and its innovative medicines are used by millions of patients worldwide. In Canada, we employ more than 675 employees across the country and our headquarters are located in Mississauga, Ontario. For more information, please visit the company's website at http://www.astrazeneca.ca.

References

SOURCE AstraZeneca Canada Inc.

For further information: AstraZeneca Corporate Communications, [emailprotected]; Hibaq Ali, Weber Shandwick Canada, [emailprotected] / tel: 416-642-7915

http://www.astrazeneca.ca

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Contemporary Bone Alleviates Mechanisms Have Prospective Therapeutic Applications – MENAFN.COM

By daniellenierenberg

(MENAFN - Fior Markets)

Spearheaded by researchers at Baylor College of Medicine divulges a contemporary mechanism that donates to adult bone conservation and restores and unfurls the possibility of advancing the therapeutic plan of action for enhancing bone healing.

Corresponding author Dr. Dongsu Park professor of molecular and human genetics said that adult bone repairs depend on the setting off of bone stem cells which yet remains deficiently distinguished. Bone stem cells have been discovered both in the bone marrow interior of the bone and also in the periosteum the exterior layer of the tissue that wraps the bone. Former studies have portrayed that these two communities of stem cell albeit they apportion various characteristics also have distinctive functions and particular regulatory processes.

Of the two periosteal steam cells are the minimalistcomprehended. It is known that they constitute a heterogeneous population ofcells that can bestow to bone density, molding and rupture restoration,however, scientists had not been able to discern between varied subtypes of thebone stem cell to scrutinize how their varied purposes are controlled.

In the present study Park and his colleagues advanced aprocedure to recognize varied subpopulations of periosteal stem cells expoundtheir benefaction to bone fracture restoration in animate mouse models andrecognize particular components that control their migration and multiplicationunder psychological circumstances.

The researchers found particular trademarks for periosteal stem cells in mouse models. The trademarks recognized a definite subset of stem cells that donates to long-lasting adult bone resurrection.

MENAFN07012020007010660ID1099519082

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London charities scoop share of 120000 festive financial boost – London Post

By daniellenierenberg

Fourteen charities based in London have won a 1,000 festive boost thanks to nominations from the public.

The charities were nominated to win a share of 120,000 as part of specialist insurer Ecclesiasticals annual 12 days of giving Christmas campaign.

Anthony Nolan, which helps to save lives by matching individuals willing to donate their blood stem cells or bone marrow to people with blood cancer and blood disorders, and Shakespeare Schools Foundation, which helps thousands of young people from across the UK become better at teamwork, more confident and more ambitious (see notes for full list1), are among the local charities set to benefit from the money, following overwhelming public support in the area.

More than 120,000 people around the UK nominated a cause close to their heart, with over 5,000 charitable causes up and down the country receiving votes. The 120 winning charities were picked at random from those nominated.

The full list of the 120 charity winners is available to view online at http://www.ecclesiastical.com/12days

Thanking supporters in London, Mark Hews, group chief executive at Ecclesiastical, said: Here at Ecclesiastical, our core purpose is to contribute to the greater good of society, so charitable giving is at the heart of our business. We know that 1,000 can make a huge difference to the incredible work that charities do and were looking forward to seeing how this festive financial boost will change lives for the better.

Last year, Ecclesiastical launched its second Impact Report to celebrate some of the many good causes it has helped.

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Gracell Initiates Investigational Study of the Technological Breakthrough TruUCAR Therapy for Relapsed or Refractory T-cell Malignancies – PRNewswire

By daniellenierenberg

SUZHOU, Chinaand SHANGHAI, Jan. 7, 2020 /PRNewswire/ -- Gracell Biotechnologies Co., Ltd. ("Gracell"), a clinical-stage immune cell therapy company, today announced the initiation of an investigational study of GC027, the first product candidate developed using TruUCAR to treat relapsed or refractory (R/R) T-cell malignancies.

T-cell acute lymphoblastic leukemia or T-ALL is an aggressive form of ALL, which affects white blood cells and the bone marrows ability to generate healthy blood cells. About 15-20% of people with ALL have T-ALL. While T-ALL is treatable by chemotherapy and stem cell transplant, around 75% of patients will relapse within two years[1]. T-cell lymphoblastic lymphoma (T-LBL) is another devastating T-cell malignancies. For patients who develop R/R T-ALL or T-LBL, there are few options for treatment.

Autologus CAR-T therapies rely on patients' own T cells, which have been affected by prior therapies; thus, cell quality as well as efficacy remains questionable. Allogenic CAR-T therapies made of healthy donors' T cells would be characterized as being of consistently good quality with the potential to improve efficacy. Unlike autologous CAR-T cells, allogeneic CAR-T cells can be made as off-the-shelf product which means patients do not have to wait for lengthy production time. Furthermore, the cost of production can be significantly lower. Allogenic CAR-T therapies also provide a vital treatment option for patients with viral infections and/or other conditions prohibiting access to autologous cell therapies.

TruUCARbased GC027 is designed to meet the above unmet needs. Its cells are made of T cells from healthy donors, genetically edited and inserted with chimeric antigen receptor (CAR) ex vivo, which can specifically bind to and eliminate target T malignant cells. Different from industry leaders' off-the-shelf CAR-T design, Gracell's proprietary and patented TruUCAR technology requires no co-administration of anti-CD52, a cytotoxic agent for ablating cancerous cells while inducing long term immune depletion in the patient.Instead, GC027 utilizes CRISPRgenome editing strategy that is expected to avoid graft-versus-host disease (GvHD) as well as graft rejection caused by the patients' immune system.

The prudent preclinical studies provide substantial evidence to trigger GC027 moving into a non-IND(investigational new drug)clinical trial to evaluate the safety, pharmacokinetics and pharmacodynamics of GC027 therapy in patients suffering from relapsed and refractory T lymphocyte malignancies.

TruUCAR is another technological breakthrough developed by Gracell following the recent announcement of FasTCAR technology and products. It enables producing off-the-shelf CAR-T cells from healthy MHC (major histocompatibility complex) mismatched donors with a large number of doses readily to be dispatched to patients in need.

"Launch of the investigational GC027 study as the first-of-its-kind therapy marks another significant milestone for Gracell," said Dr. William CAO, Founder and CEO of Gracell. "Once the concept is well-proved with solid evidence for safety and efficacy, we will immediately deploy development of a series of TruUCAR products for other medical unmet needs, including B cell malignancies."

About GC027

GC027 is an investigational, off-the-shelf CAR-T cell therapy for T cell malignancies, derived from healthy donors. The use of healthy donor's cells are preferential to a patient's own with potential to improve efficacy, reduce production time, and lower cost of goods.

About T-ALL

T lymphoblastic leukemia (T-ALL) is an aggressive form of T cell malignancies, with a diffuse invasion of bone marrow and peripheral blood. In 2015, ALL affected around 876,000 people globally and resulted in 110,000 deaths worldwide. T-ALL compromises about 15%-20% children and adults[1].Current standard therapies for T-ALL are chemotherapies and stem cell transplantation. A large portion of these patients will experience relapse within two years following treatment by conventional therapies.

About T-LBL

T lymphoblastic lymphoma (T-LBL) is an aggressive form of T cell malignancies, with rare lymphoproliferative neoplasm of mature T cells caused by infection with the retrovirus human T lymphotropic virus. T-LBL compromises about 2% of adult non-Hodgkin's lymphoma (NHL) and 30% of pediatric NHL patients[2]. Five-year overall survival is only 14% in adults.Although first-line treatment using cytotoxic combination chemotherapy can achieve 70% ORR, nearly 90% of patients relapse, often within months of completing chemotherapy.

About Gracell

Gracell Biotechnologies Co., Ltd. ("Gracell") is a clinical-stage biopharma company, committed to developing highly reliable and affordable cell gene therapies for cancer. Gracell is dedicated to resolving the remaining challenges in CAR-T, such as high production costs, lengthy manufacturing process, lack of off-the-shelf products, and inefficacy against solid tumors. Led by a group of world-class scientists, Gracell is advancing FasTCAR, TruUCAR (off-the-shelf CAR), Dual CAR and Enhanced CAR-T cell therapies for leukemia, lymphoma, myeloma, and solid tumors.

CONTACT:

[1]Pediatric hematologic Malignancies: T-cell acute lymphoblastic Leukemia, Hematology 2016

[2]Clinical Review: Adult T-cell Leukemia/lymphoma, Journal ofOncology Practice 2017

SOURCE Gracell

http://www.gracellbio.com

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BrainStorm Cell Therapeutics to Present at the 2020 Biotech Showcase and 3rd Annual Neuroscience Innovation Forum at JPM Week – Yahoo Finance

By daniellenierenberg

NEW YORK, Jan. 07, 2020 (GLOBE NEWSWIRE) -- BrainStorm Cell Therapeutics Inc. (BCLI), a leading developer of adult stem cell therapeutics for neurodegenerative diseases, announced today that Chaim Lebovits, President and Chief Executive Officer, will provide a corporate overview at the 2020 Biotech Showcase, being held on January 13-15, 2020 at the Hilton San Francisco Union Square in San Francisco, California.

Mr. Lebovits will also present at the 3rd Annual Neuroscience Innovation Forum, taking place on January 12, 2020, at the Marines Memorial Club in San Francisco. Additionally, Ralph Kern M.D., MHSc, BrainStorms Chief Operating Officer and Chief Medical Officer, will participate on aRare & Orphan Diseases Panel.

Meetings

BrainStorms senior management will also be hosting institutional investor and partnering meetings at the 2020 Biotech Showcase conference (https://goo.gl/SGFm62). Please use the Investor contact information provided below to schedule a meeting.

About NurOwn

NurOwn (autologous MSC-NTF cells) represent a promising investigational approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors. Autologous MSC-NTF cells can effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression. NurOwn is currently being evaluated in a Phase 3 ALS randomized placebo-controlled trial and in a Phase 2 open-label multicenter trial in Progressive MS.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug status designation from the U.S. Food and Drug Administration (U.S. FDA) and the European Medicines Agency (EMA) in ALS. BrainStorm has fully enrolled a Phase 3 pivotal trial in ALS (NCT03280056), investigating repeat-administration of autologous MSC-NTF cells at six sites in the U.S., supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). The pivotal study is intended to support a filing for U.S. FDA approval of autologous MSC-NTF cells in ALS. For more information, visit BrainStorm's website at http://www.brainstorm-cell.com.

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could causeBrainStorm Cell Therapeutics Inc.'sactual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may", "should", "would", "could", "will", "expect", "likely", "believe", "plan", "estimate", "predict", "potential", and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorms need to raise additional capital, BrainStorms ability to continue as a going concern, regulatory approval of BrainStorms NurOwn treatment candidate, the success of BrainStorms product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorms NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorms ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorms ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation,; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

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Cynata Therapeutics (ASX:CYP) receives R&D tax incentive refund of more than $1.8M – The Market Herald

By daniellenierenberg

Cynata Therapeutics (CYP) has received a research and development tax incentive refund of $1,891,795 for the 2018-2019 financial year.

This tax incentive refund increases the company's cash position which stood at $9.2 million at the end of the September quarter.

It also enables further resources to be invested towards Cynata's phase 2 clinical trial programs for the critical limb ischemia (CLI) (reduced blood flow) and osteoarthritis products.

This will be alongside the anticipated phase 2 trial for CYP-001 in graft-versus-host disease which will be conducted by Fujifilm.

CLI is an advanced stage of peripheral artery disease which is the narrowing of the arteries in the limbs, typically in the lower legs.

It results from severely impaired blood flow which can cause pain, tissue damage, and gangrene.

Around 25 per cent of CLI patients who are unable to undergo surgery to remove the affected area, often an amputation, will die within a year of diagnosis.

Cynata' Cymerus mesenchymal stem cells (MSCs) have been successfully tested in a mouse model of CLI.

Muscles on the ischaemic leg were injected with Cymerus MSCs or a control.

Over a four-week follow-up period, the return of blood flow was measured and in animals treated with Cymerus MSCs blood flow in the injured limb was significantly higher at every point compared to the control.

MSCs are an adult stem cell found in a wide range of human tissues including bone marrow, fat tissue and placenta.

They are multi-potent which means they can produce more than one type of cell, for example they can differentiate into cartilage cells, bone cells and fat cells.

MSCs have been shown to ease regeneration and effects on the immune system without relying on engraftment (when the transplanted cells start to grow and make healthy cells).

The research and development tax incentive is an important Australian Government program that encourages companies to engage in research and development benefiting Australia by providing a tax offset for eligible activities.

Cynata's share price is up a steady 4.82 per cent with shares trading for $1.20 apiece at 3:29 pm AEDT.

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The supercells’ that cured an infants genetic illness – Jamaica Observer

By daniellenierenberg

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MCLEAN, United States (AFP) When a person's immune system is impaired by a genetic disease a bone marrow transplant can be a powerful therapeutic tool, but with a major downside during the first few months the recipient's defences against viruses are severely weakened. The slightest infection can lead to a hospital trip.

A still-experimental type of treatment known as T-cell therapy aims to assist during this vulnerable period the months during which the body is rebuilding its natural defences. After two decades of clinical trials, the technology has been refined and is being used to treat more and more patients, many of them children.

A boy named Johan is one of them.

Today he is a mischievous, smiling toddler, with a thick shock of light-brown hair, who never tires, playfully tormenting the family's puppy, Henry.

There is no sign of the three-year-long medical and emotional roller coaster ride he and his family, who live in an affluent Washington suburb, have been on.

The first traumatic surprise came with the results of a pregnancy test Johan was not planned.

That was a huge shock. I cried, said his mother, 39-year-old Maren Chamorro.

Risky procedure

She had known since childhood that she carried a gene that can be fatal in a child's first 10 years, chronic granulomatous disease (CGD).

Her brother died of it at the age of seven. The inexorable laws of genetics meant that Maren had a one in four chance of transmitting it to her child.

For their first children, she and her husband Ricardo had chosen invitro fertilisation, allowing the embryos to be genetically tested before implantation.

Their twins Thomas and Joanna were born both disease-free seven and a half years ago.

But in Johan's case, a post-birth genetic test quickly confirmed the worst: He had CGD.

After conferring with experts at Children's National Hospital in Washington, the couple took one of the most important decisions of their lives, Johan would receive a bone marrow transplant a risky procedure but one that would give him a chance of a cure.

Obviously, the fact that Maren had lost a sibling at a young age from the disease played a big role, Ricardo confided.

Bone marrow, the spongy tissue inside bones, serves as the body's factory for the production of blood cells both red and white.

His brother's immune system

Johan's white blood cells were incapable of fighting off bacteria and fungal infections. A simple bacterial infection, of negligible concern in a healthy child, could spread out of control in his young body.

Luckily, Johan's brother Thomas, six years old at the time, was a perfect match. In April 2018, doctors first cleansed Johan's marrow using chemotherapy. They then took a small amount of marrow from Thomas's hip bones using a long, thin needle.

From that sample they extracted supercells, as Thomas calls them stem cells, which they reinjected into Johan's veins. Those cells would eventually settle in his bone marrow and begin producing normal white blood cells.

The second step was preventive cell therapy, under an experimental programme led by immunologist Michael Keller at Children's National Hospital.

The part of the immune system that protects against bacteria can be rebuilt in only a matter of weeks; but for viruses, the natural process takes at least three months.

Hurdles remain

From Thomas's blood, doctors extracted specialised white blood cells T-cells that had already encountered six viruses.

Keller grew them for 10 days in an incubator, creating an army of hundreds of millions of those specialised T-cells. The result: A fluffy white substance contained in a small glass vial.

Those T-cells were then injected into Johan's veins, immediately conferring protection against the six viruses.

He has his brother's immune system, said Keller, an assistant professor at Children's National.

Johan's mother confirmed as much: Today, when Thomas and Johan catch a cold they have the same symptoms, and for nearly the same amount of time.

I think it's pretty cool to have immunity from your big brother, Maren Chamorro said.

This therapeutic approach boosting the body's immune system using cells from a donor or one's own genetically modified cells is known as immunotherapy.

Its main use so far has been against cancer, but Keller hopes it will soon become available against viruses for patients, like Johan, who suffer from depressed immune systems.

The chief obstacles to that happening are the complexity of the process and the costs, which can run to many thousands of dollars. These factors currently restrict the procedure to some 30 medical centres in the United States.

For Johan, a year and a half after his bone marrow transplant, everything points to a complete success.

It's neat to see him processing things, and especially play outside in the mud, his mother said.

You know, what a gift!

Her only concern now is the same as any mother would have that when her son does fall ill, others in the family might catch the same bug.

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Bone marrow donor’s amazing 30 year bond with man he saved – Mirror Online

By daniellenierenberg

There was a head-scratching moment when Martin Swales answered his front door and a priest handed him a letter.

The mystery was quickly solved. It contained a thank you note from someone whose life Martin had saved.

He knew his bone marrow had been given to someone called Jan and imagined it was a woman in Britain.

In fact the recipient was dad Jan Zemek 4,500 miles away in the US.

And Martins gift of life has led to an extraordinary 30-year bond between the pair, who are like blood brothers.

Jan named his second daughter Martina in honour of his hero and Martin is godfather to his third girl.

Retired welder Martin, 58, of Guisborough, North Yorks, said: Donating bone marrow didnt just save Jans life, it changed mine as well.

The first time I met Jan, I put my arms around him and he hugged me back.

It felt natural, like I was welcoming my brother. It feels like our two families have become one.

They each have three grown-up children and have visited each other for baptisms, graduations, and weddings.

Martin recently went to Switzerland, where Jan lives with his family, to celebrate 30 years since the transplant and present his blood brother with a Walk of Fame plaque.

It includes the touching message: Stood strong, fought hard, and won. You are a survivor.

The mens amazing and heart-warming story dates from 1986 when Martin joined the Anthony Nolan stem cell register after an appeal to save two girls living in the North East.

He was not a match for the girls but in 1989 was called by the register because he could be for Jan.

Martin said: It was quite a shock because Id pretty much forgotten about the register. They told me I was a possible match for someone and what was involved. I said yes straight away. I wanted to help if I could.

Despite the discomfort, Martin gave bone marrow from his hip at a clinic in Harley Street that August. Doctors extracted it from inside his hip using a long needle. Today most donations are no more invasive than giving blood.

Martin spent two nights in hospital. He said: It doesnt take long but at the time I was suffering from sciatica so I think I found it a bit more painful than most. It was an uncomfortable journey home on the train.Anthony Nolan covered the cost of the trip.

Jan, a 27-year-old dad, was diagnosed with leukaemia in 1987. Initially doctors kept the news from him as no treatment was available in the Czech Republic, where he lived.

Jan said: I was diagnosed one year after the Chernobyl tragedy, weve never known if that radiation was to blame for my cancer. I suddenly grew very tired, nobody knew the reason.

I didnt know how sick I was because the doctors wouldnt tell me.

My wife, who was then my girlfriend, went to the same doctors and they told her, Dont marry this guy, dont have children with him. He is going to die in two years.

But Radka ignored their warning and insisted on marrying Jan in 1987.

His only hope was a bone marrow transplant. Weeks later he left for the US with his dad, who planned to be his donor.

Jan said: A few months earlier, I read in the paper the opera singer Jos Carreras was diagnosed with a similar blood disease and was going to the same US centre for a transplant.

They arrived with less than 40 in their pockets and discovered a transplant from his dad would give Jan only a 15 per cent chance of survival.

Instead doctors advised them to find a donor. It took two years and 10,000 to test potential donors before they found a perfect match in Martin.

By then Jan and Radka had become parents to their first daughter, Jana.

Jan needed to raise more than 100,000 to fund the transplant.

He said: It was such a huge amount of money to raise but when you are dying you have no choice.

There were 12 rival local radio stations but they all got together to run a joint appeal, which they broadcast at the same time. It was incredible.

Jan did a sponsored run, gave talks about his ordeal to church congregations to request donations, and wrote to celebrities, especially those with links to the Czech Republic.

Donald Trump s ex-wife Ivana gave 1,000, as did One Flew Over the Cuckoos Nest director Milos Forman. Jan said: The response was crazy. So many people donated 20 dollars or 50.

Martins bone marrow was flown to the Fred Hutchinson Cancer Research Center in Seattle, where Jan was waiting in an isolation room.

He had been blasted with chemo and radiotherapy so his immune system would not attack Martins transplanted cells.

Normally, under strict anonymity rules to protect donor and recipient, Martin and Jan would have been unable to contact each other for years.

But a priest from the North East of England working at the hospital recognised Martins address when the bag of bone marrow arrived.

He offered to take a photo of Jan, a thank you letter, and a Czech garnet stone to Martin when he returned home in 1990.

Martin said: I was stunned. I had no idea my bone marrow had travelled so far. Knowing Id helped a young father, just like me, brought home how important it was and how easily it could have been me waiting for a stranger to save my life.

I wrote straight back. The priest also brought a letter from a couple whose daughter was in the same hospital.

Her transplant didnt work. Sadly she died, but they wrote to thank me for saving Jan. Responding to them was much harder. How do you find the right words?

Martin and Jan kept in touch. When Jans second daughter was born in 1991, he and Radka named her after Martin.

Jan said: How do you repay someone who saved your life? Naming our daughter after Martin was our way of showing him we would never forget what he did for us.

Hes not just the man who saved my life. He is a nice guy. Thats why were so close.

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Jan, 59, and his family moved to Switzerland, where he landed a job with a sports marketing firm that works with World Athletics.

In 1992 his job brought him to Crystal Palace in South London and he spent a few days with Martin and family.

Jans youngest daughter Michaela was born in 1995 and he invited Martin and his family to Switzerland for the baptism and asked him to be godfather.

The two families continued to visit each other and holidayed together in the Czech capital Prague. When Jans eldest, Jana, was studying at Newcastle University, she regularly spent weekends with Martin and his wife Tracey.

Martin said: It meant so much to visit Jan for the 30 anniversary of his transplant earlier this year.

"They showed us the sights and we went up the mountains. It was brilliant. I could never have imagined this when I joined the stem cell register all those years ago.

He added: I hope Martin and I will be able to celebrate another anniversary together in ten years.

The Anthony Nolan register matches potential donors to patients needing stem cell transplants and does vital research. To join, donate or find out more, see anthonynolan.org .

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Gene editing breakthroughs that cured genetic diseases in 2019 – The Star Online

By daniellenierenberg

IN the summer of 2019, a mother in Nashville, Tennessee in the United States, with a seemingly incurable genetic disorder finally found an end to her suffering by editing her genome.

Victoria Grays recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research gene therapy.

I have hoped for a cure since I was about 11, the 34-year-old said.

Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency.

Over several weeks, Grays blood was drawn so that doctors could get to the cause of her illness stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 pronounced Crisper a new tool informally known as a molecular scissors.

The genetically-edited cells were transfused back into Grays veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary, but theoretically, she has been cured.

This is one patient. This is early results. We need to see how it works out in other patients, said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

But these results are really exciting.

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease beta thalassemia.

She had previously needed 16 blood transfusions per year. Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified. But Crispr, invented in 2012, made gene editing more widely accessible.

It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

Its all developing very quickly, said French geneticist Emmanuelle Charpentier, one of Crisprs inventors and the co-founder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Gene cures

Crispr was the latest breakthrough in a year of great strides in gene therapy, a medical adventure that started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practising the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not, such as making normal red blood cells in Grays case or making tumour-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union.

They join several other gene therapies bringing the total to eight approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

Twenty-five, 30 years, thats the time it had to take, he said. It took a generation for gene therapy to become a reality. Now, its only going to go faster.

Just outside Washington, at the US National Institutes of Health (NIH), researchers are also celebrating a breakthrough period.

We have hit an inflection point, said US NIHs associate director for science policy Carrie Wolinetz.

These therapies are exorbitantly expensive, however, costing up to US$2 million (RM8.18 million) meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion and fighting a general infection.

You cannot do this in a community hospital close to home, said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to Massachusetts Institute of Technology (MIT) researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

In this Oct 10, 2018, photo, He speaks during an interview at his laboratory in Shenzhen, China. The scientist was recently sentenced to three years in prison for practicing medicine illegally and fined 3 million yuan (RM1.76 million). AP

Bioterrorism potential

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who dont necessarily share the medical ethics of Western medicine.

In 2018 in China, scientist He Jiankui triggered an international scandal and his excommunication from the scientific community when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA (deoxyribonucleic acid) of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV (human immunodeficiency virus), even though there was no specific reason to put them through the process.

That technology is not safe, said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr scissors often cut next to the targeted gene, causing unexpected mutations.

Its very easy to do if you dont care about the consequences, he added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species, e.g. malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesnt believe in the more dystopian scenarios predicted for gene therapy, including American biohackers injecting themselves with Crispr technology bought online.

Not everyone is a biologist or scientist, she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies crops?

Charpentier thinks that technology generally tends to be used for the better.

Im a bacteriologist -- weve been talking about bioterrorism for years, she said. Nothing has ever happened. AFP Relaxnews

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My agonising two-year wait for a stem-cell donor after being diagnosed with leukaemia – The Telegraph

By daniellenierenberg

There is also another option on the table: a technology called haplo-identical, where they could use the stem cells from my brother, who is a 50 per cent match.

But it shouldnt have been this hard to find a match, and thats whyI started my campaign to sign more people up to the transplant list.I want to make a difference for other people who have to go through this.

If I dont make it, I want to leave a legacy that the children can look at when theyre older and know that Mummy did everything she could to fight this thing. There can only be one winner with this disease, and it needs to be me.

As told to Jessica Salter

Leukaemia Care is one of three charities supported by this years Telegraph Christmas Charity Appeal. Our others are Wooden Spoon, which works with the rugby community to raise money for disabled and disadvantaged children,and The Silver Line, a telephone support service for lonely elderly people. To donate,visit telegraph.co.uk/charity or call 0151 284 1927 before the end of January

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BrainStorm Cell Therapeutics Wins 2020 ‘Buzz of BIO’ Award for ALS Investigational Therapy – ALS News Today

By daniellenierenberg

For its promising investigational therapeutic approach to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), BrainStorm Cell Therapeutics is theBuzz of BIO 2020 winnerin the Public Therapeutic Biotech category.

The Buzz of BIO contest identifies U.S. companies with groundbreaking, early-stage potential to improve lives. The event also is anopportunity to make investor connections that could take products to the next phase.

Ten biotechnology companies are nominated in each of the three categories ofBuzz of BIO: Public Therapeutic Biotech, Private Therapeutic Biotech, and Diagnostics and Beyond. In the Public Therapeutic Biotech category that BrainStorm won, nominated companies must be actively developing a publicly traded human treatment intended for review by theU.S. Food and Drug Administration (FDA).

As a developer of autologous cellular therapies treatments that use a patients own cells and tissues for debilitating neurodegenerative diseases, BrainStorm is now testing its NurOwn therapy for safety and effectiveness. The treatment involves extracting, from human bone, marrow-derived mesenchymal stem cells (MSCs), which are capable of differentiating into other cell types. The MSCs are then matured into a specific cell type that produces neurotrophic factors compounds that promote nervous tissue growth and survival. They are then reintroduced to the body via injection into muscles and/or the spinal canal.

Backed by a California Institute for Regenerative Medicine grant, Brainstorm has fully enrolledits randomized, double-blind, placebo-controlled Phase 3 clinical trial (NCT03280056) at six U.S. sites in California, Massachusetts, and Minnesota. Some 200 ALS patients are participating. A secondary safety analysis by the trials independent Data Safety Monitoring Board (DSMB) revealed no new concerns. Every two months, study subjects will be given three injections into the spinal canal of either NurOwn or placebo.

The trial is expected to conclude late this year. Results will be announced shortly afterward.

In a Phase 2 study (NCT02017912), which included individuals with rapidly progressing ALS, NurOwn demonstrated a positive safety profile as well as prospective efficacy.

The use of autologous MSC cells to potentially treat ALS was given orphan drug status by both the FDA and the European Medicines Agency.

Thanks to everyone who voted for BrainStorm during the Buzz of BIO competition,Chaim Lebovits, BrainStorm president and CEO, said in a press release. The entire management team at BrainStorm was very pleased with the results of this competition, and we look forward to presenting to an audience of accredited investors who may benefit from the companys story. We thank the BIO[Biotechnology Innovation Organization] team for singling out BrainStorms NurOwn as a key technology with the potential to improve lives.

As a contest winner, BrainStorm is invited to givea presentation at theBio CEO & Investor Conference, to be held Feb. 1011 in New York City, along with exposure to multiple industry elites and potential investors.

NurOwn cells also are being tested in a Phase 2 clinical study (NCT03799718) in patients with progressive multiple sclerosis.

Mary M. Chapman began her professional career at United Press International, running both print and broadcast desks. She then became a Michigan correspondent for what is now Bloomberg BNA, where she mainly covered the automotive industry plus legal, tax and regulatory issues. A member of the Automotive Press Association and one of a relatively small number of women on the car beat, Chapman has discussed the automotive industry multiple times of National Public Radio, and in 2014 was selected as an honorary judge at the prestigious Cobble Beach Concours dElegance. She has written for numerous national outlets including Time, People, Al-Jazeera America, Fortune, Daily Beast, MSN.com, Newsweek, The Detroit News and Detroit Free Press. The winner of the Society of Professional Journalists award for outstanding reporting, Chapman has had dozens of articles in The New York Times, including two on the coveted front page. She has completed a manuscript about centenarian car enthusiast Margaret Dunning, titled Belle of the Concours.

Total Posts: 6

Ins holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Cincias e Tecnologias and Instituto Gulbenkian de Cincia. Ins currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.

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ASTRONOMICAL ODDS: Stem cell recipient and her donor both from Ottawa – Ottawa Sun

By daniellenierenberg

Colleen LeCours lay in a hospital bed at the General campus of The Ottawa Hospital on August 12, 2016, waiting for the only thing that could save her life a stem cell transplant from a stranger.

The donor could be anywhere in the world if a related blood donor cant be found, the call to find a match goes out to registries all over the globe and the donated stem cells are rushed across international borders.

What LeCours didnt know is that her donor, an 18-year-old Carleton University student named Timothy White, was just one floor below. Similarly, White didnt know that his recipient was in the same hospital.

There are currently more than 450,000 people on the Canadian Blood Services Stem Cell Registry formerly known as OneMatch and 36 million on affiliated international registries. Still, some people never find a match. There are more than 900 Canadians in need of a transplant who have not found a match anywhere in the world.

What were the odds that the match for LeCours, now 57, would be found in the same city?

Astronomical, she said.

The chances that White would even ever be asked to donate were also very low only about one in a thousand. After he agreed to donate, he was not told where the recipient might be. I was told the recipient could be anywhere. They could be in Africa, said White, now 22 and a recent graduate in computer science.

White had signed up for the registry through a cheek swab booth at ComiCon less than six months earlier. A smart place to recruit would-be stem cell donors, he notes. The optimal donor is a male between the age of 17 and 35 and thats the ComiCon demographic.

He decided to register as a potential donor because he grew up in the scouting movement. One of the main philosophies is to do a good turn every day, he said.

The donation was a non-surgical procedure in which Whites blood was removed though a needle, the stem cells were separated from his blood and the remaining blood components returned to his body through another needle. The procedure started at about 8 a.m. and was over by about 5 p.m.

I figured if I gave someone a day for a thousand more days (of life) then I felt it was a fair trade. I have many years of life. Why not spend one day? said White.

LeCourss medical journey started in 2009 with an emergency room visit for abdominal pain. She was eventually diagnosed with Stage 4 follicular lymphoma, a blood cancer that affects infection-fighting white blood cells. At the time, LeCours was working for Gov.-Gen. Michalle Jean and was able to stay on the job most of the time during her six months of treatment.

Four years later, the lymphoma returned. It was back again two years after that, in a more aggressive form. The only treatment was stem cell transplant.

There are two main kinds of stem cell transplants autologous and allogenic. In an autologous transplant, stem cells are collected from a patients own blood and reintroduced after being treated to remove cancer cells. In an allogenic stem cell transplant, the stem cells come from a donor.

At this point, LeCours was a candidate for an autologous transplant. Once again, she underwent aggressive chemotherapy. A year later, the cancer returned.

Doctors told LeCours there wasnt much else they could do and advised her to get her affairs in order. But the hospitals transplant team felt she could be a candidate for an allogenic transplant. Theres risk rejecting donated stem cells can be fatal to the patient.

LeCours learned that her brother was a match. But the medical work-up would last about three months and she couldnt wait that long.

I wasnt sure I wanted to do it but I didnt have much choice, she said. They said, We have someone waiting in the wings.

And I said, He probably has wings.

After the transplant, LeCours recovered as an outpatient in the home of her brother and sister-in-law. It took three months to rebuild her immune system. Her only rejection symptoms were a bit of skin irritation.

In January 2018, LeCours received an email asking if she would like to exchange contact information with her donor. She replied that she would.

A few months later, she got a message with Whites co-ordinates and was astonished to find that her donor was in Ottawa. It took her a few weeks to formulate an email.

I didnt want to scare him. I just wanted him to know how incredibly grateful I was. And I wanted to pay it forward, said LeCours.

After careful consideration, she sent White an email on Oct. 8, 2018.

Today, being Thanksgiving, I have so much to be thankful for, namely you giving your stem cells and saving my life and the success of the stem cells grafting to my bone marrow, LeCours wrote. I cant thank you enough for your wonderful selfless act.

Stem cell donor 18-year-old Carleton University student Timothy White at The Ottawa Hospital, General campus, donating stem cells for Colleen LeCours in August 2016. At the time he did not know that LeCours would be the recipient. Courtesy Timothy White.jpg

She added that she didnt know anything about him except for his name and email address, and asked if they could meet. They got together for the first time over lunch in a burger restaurant.

As soon as I saw him, I broke down, said LeCours.

It has been three and a half years since the transplant and LeCours remains in remission. She invited White to her familys Thanksgiving this year, and the two meet to catch up every few months. Its one of the quirks of stem cell donation that the recipient assumes the blood type of the donor. LeCours, once O-positive, now has blood type A-negative, like White.

Im a grandmother. The fact that my grandson has his moma is huge.

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Stocks making the biggest moves midday: L3Harris, Tesla, Apache & more – CNBC

By daniellenierenberg

Military personnel walk past the Raytheon Missile stand.

Carl De Souza | AFP | Getty Images

Check out the companies making headlines in midday trading:

Raytheon, Lockheed Martin, L3Harris Equity of major aircraft and weapons manufacturers Raytheon, Lockheed Martin and L3Harris rose 1.6%, 3.8% and 3.3%, respectively, in midday trading as U.S.-Iranian tensions flare in the Middle East. The U.S. confirmed it was responsible for a drone strike in Baghdad on Friday that killed Iranian Gen. Qasem Soleimani, Tehran's top military commander and a prominent political fixture in the region.

Incyte Shares of Incyte plunged 10% Friday after the company announced that a Phase III study showed one of its developmental drugs failed to show results that were statistically superior to a placebo. The drug was aimed at treating a disease that arises when donated bone marrow or stem cells attack their new host.

Tesla Tesla's stock climbed 3.8% on Friday after the automaker reported better-than-expected deliveries for its most recent quarter. The electric car company delivered 112,000 vehicles during the fourth quarter, topping consensus estimates of 106,000. Tesla delivered roughly 367,500 vehicles for the full year, a 50% increase from 2018 and within the range that it had given as guidance.

Bank of America Shares of the top U.S. bank fell 1.5% in afternoon trading after BMO Capital Markets downgraded the equity to market perform from outperform, telling clients its valuation re-rating has "run its course." Analyst James Fotheringham added that Bank of America shares now trade at a premium to their long-term average and suggested investors look to cheaper names like Citi and Morgan Stanley in the big-bank space.

Concho Resources, Apache, Devon Energy Shares of Concho, Apache and Devon all traded higher, following crude prices, after the U.S. killed a top Iranian military leader in an airstrike. Concho and Apache each traded higher by more than 1% while Devon advanced 0.8%.

L Brands Shares of L Brands rose nearly 8% after Bank of America upgraded the retail and apparel company to buy from neutral. The bank's analysts cited a strong Bath & Body Works business, potential for a more stable Victoria's Secret and a high dividend yield as reasons for the upgrade. The bank also raised its price target on the stock to $25 per share from $21, which would be a 49% increase from where the stock closed on Thursday.

Humana Humana rose 1.5% after Goldman Sachs added the health care company to its "Conviction Buy" list and told clients it sees sizable upward revisions to earnings estimates due to the recent repeal of a fee on health insurers.

CNBC's Fred Imbert and Jesse Pound contributed to this report.

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Stocks making the biggest moves midday: L3Harris, Tesla, Apache & more - CNBC

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Targeted deletion of PD-1 in myeloid cells induces antitumor immunity – Science

By daniellenierenberg

INTRODUCTION

Programmed cell death protein 1 (PD-1) is a major inhibitor of T cell responses expressed on activated T cells. It is also expressed on natural killer cells, B cells, regulatory T cells, T follicular helper cells, and myeloid cells (1). The current model supports that a key mechanism dampening antitumor immune responses is the up-regulation of PD-1 ligands in cancer cells and antigen-presenting cells (APCs) of the tumor microenvironment (TME), which mediate ligation of PD-1 on tumor-infiltrating CD8+ T cells, leading to the development of T incapable of generating antitumor responses (2). Therapeutic targeting of the PD-1 pathway with antibodies blocking the PD-1 receptor or its ligands induces expansion of oligoclonal CD8+ tumor-infiltrating lymphocytes that recognize tumor neoantigens (3). Thus, in the context of cancer, PD-1 is considered a major inhibitor of T effector cells, whereas on APC and cancer cells, emphasis has been placed on the expression of PD-1 ligands. PD-1 ligand-1 expression in the TME is often a prerequisite for patient enrollment to clinical trials involving blockade of the PD-1 pathway. However, responses do not always correlate with PD-L1 expression, and it remains incompletely understood how the components of the PD-1:PD-L1/2 pathway suppress antitumor immunity.

Recent studies indicated that PD-1 can be induced by Toll-like receptor (TLR) signaling in macrophages (M) and negatively correlates with M1 polarization (4). PD-1 expression in macrophages plays a pathologic role by suppressing the innate inflammatory response to sepsis (5) and inhibiting Mycobacterium tuberculosis phagocytosis in active tuberculosis (6). Our knowledge about the function of PD-1 on myeloid cells in the context of cancer is very limited. However, similar to its role in infections, PD-1 expression inversely correlates with M1 polarization and phagocytic potency of tumor-associated M (TAM) against tumor (7, 8). The mechanisms of PD-1 expression in myeloid cells and the role of PD-1expressing myeloid cells in tumor immunity remain unknown.

The rapid increase in myeloid cell output in response to immunologic stress is known as emergency myelopoiesis. Terminally differentiated myeloid cells are essential innate immune cells and are required for the activation of adaptive immunity. Strong activation signals mediated by pathogen-associated molecular pattern or danger-associated molecular pattern molecules lead to a transient expansion and subsequent differentiation of myeloid progenitors to mature monocytes and granulocytes to protect the host. In contrast, during emergency myelopoiesis mediated by continuous low-level stimulation mediated by cancer-derived factors and cytokines, bone marrow common myeloid progenitors (CMPs) but, predominantly, granulocyte/macrophage progenitors (GMPs) undergo modest expansion with hindered differentiation, and a fraction of myeloid cells with immunosuppressive and tumor-promoting properties, named myeloid-derived suppressor cells (MDSCs), accumulates. MDSCs suppress CD8+ T cell responses by various mechanisms (9). In the mouse, MDSCs consist of two major subsets, CD11b+Ly6ChiLy6G (thereafter named CD11b+Ly6C+) monocytic (M-MDSC) and CD11b+Ly6CloLy6G+ (hereafter named CD11b+Ly6G+) polymorphonuclear (PMN-MDSC) (10). These cells have similar morphology and phenotype to normal monocytes and neutrophils but distinct genomic and biochemical profiles (9). In humans, in addition to M-MDSC and PMN-MDSC, a small subset of early-stage MDSC has been identified (10).

Although PMN-MDSCs represent the major subset of circulating MDSC, they are less immunosuppressive than M-MDSC when assessed on a per cell basis (1113). Current views support the two-signal requirement for MDSC function. The first signal controls MDSC generation, whereas the second signal controls MDSC activation, which depends on cues provided by the TME and promotes MDSC differentiation to TAM (14). Proinflammatory cytokines and endoplasmic reticulum stress response in the TME contribute to pathologic myeloid cell activation that manifests as weak phagocytic activity, increased production of reactive oxygen species and nitric oxide (NO) and expression of arginase-1 (ARG1), and convert myeloid cells to MDSC (9). MDSCs are associated with poor outcomes in many cancer types in patients and negatively correlate with response to chemotherapy, immunotherapy, and cancer vaccines (1519).

In the present study, we examined how PD-1 regulates the response of myeloid progenitors to cancer-driven emergency myelopoiesis and its implications on antitumor immunity. We determined that myeloid progenitors, which expand during cancer-driven emergency myelopoiesis, express PD-1 and PD-L1. PD-L1 was constitutively expressed on CMPs and GMPs, whereas PD-1 expression displayed a notable increase on GMPs that arose during tumor-driven emergency myelopoiesis. PD-1 was also expressed on tumor-infiltrating myeloid cellsincluding M-MDSCs and PMN-MDSCs, CD11b+F4/80+ M, and CD11c+major histocompatibility complex class II-positive (MHCII+) dendritic cells (DCs) in tumor-bearing miceand on MDSCs in patients with refractory lymphoma. Ablation of PD-1 signaling in PD-1 knockout (KO) mice prevented GMP accumulation and MDSC generation and resulted in increase of Ly6Chi effector monocytes, M and DC. We generated mice with conditional targeting of the Pdcd1 gene (PD-1f/f) and selectively eliminated PD-1 in myeloid cells or T cells. Compared with T cellspecific ablation of PD-1, myeloid-specific PD-1 ablation more effectively decreased tumor growth in various tumor models. At a cellular level, only myeloid-specific PD-1 ablation skewed the myeloid cell fate commitment from MDSC to effector Ly6Chi monocytes M and DC and induced T effector memory (TEM) cells with improved functionality. Our findings reveal a previously unidentified role of the PD-1 pathway and suggest that skewing of myeloid cell fate during emergency myelopoiesis and differentiation to effector APCs, thereby reprogramming T cell responses, might be a key mechanism by which PD-1 blockade mediates antitumor function.

For our studies, we selected the murine B16-F10 melanoma tumor model because it has been informative in dissecting mechanisms of resistance to checkpoint immunotherapy (20). First, we examined whether B16-F10 induces tumor-driven emergency myelopoiesis similarly to the MC17-51 fibrosarcoma, a mouse tumor model well established to induce cancer-driven emergency myelopoiesis (21). We assessed the expansion of myeloid progenitors in the bone marrow and the increase of CD11b+CD45+ myeloid cells in the spleen and tumor (figs. S1 and S2). Both tumor types induced increase of myeloid progenitors in the bone marrow and systemic increase of CD45+CD11b+ myeloid cells (fig. S3), providing evidence that B16-F10 melanoma is an appropriate tumor model to study tumor-driven emergency myelopoiesis and its consequences in tumor immunity. In the spleen of nontumor-bearing mice, few myeloid cells constitutively expressed very low levels of PD-L1, whereas PD-1 was very low to undetectable (Fig. 1, A and B). In B16-F10 tumor-bearing mice, expression of PD-1 and PD-L1 was up-regulated on myeloid cells of the spleen (Fig. 1, C to F). PD-1 and PD-L1 were also expressed on myeloid cells at the tumor site (Fig. 1, G to I). All subsets of myeloid cells expanding in tumor-bearing mice including M-MDSCs, PMN-MDSCs, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs expressed PD-1 (Fig. 1, D and G). Kinetics studies of PD-1 expression on myeloid cells in the spleen of tumor-bearing mice showed a gradual increase over time (Fig. 1, J to M).

(A and B) Expression of PD-1 and PD-L1 on CD11b+Ly6C+ monocytes and CD11c+MHCII+ DC in the spleen of nontumor-bearing C57BL/6 mice. FMO, fluorescence minus one. (C) C57BL/6 mice were inoculated with B16-F10 mouse melanoma, and at the indicated time points, expression of PD-1 was examined by flow cytometry in the spleen after gating on the indicated myeloid populations; contour plots depicting the percentage of positive cells are shown. On day 16 after tumor inoculation, expression of PD-1 and PD-L1 was assessed in the spleen (D) and the tumor site (G) after gating on the indicated myeloid populations. (D and G) Fluorescence-activated cell sorting (FACS) histograms and contour plots depicting the percentage of positive cells and bar graphs (E, F, H, and I) of mean SEM positive cells. Results are representative of 12 independent experiments with six mice per group. (J to M) Kinetics of PD-1 up-regulation on CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ of the spleen after tumor inoculation. **P < 0.01, ***P < 0.005, ****P < 0.001.

Because myeloid cells that give rise to MDSC and TAM are generated from myeloid progenitors in the bone marrow during tumor-driven emergency myelopoiesis, we examined PD-1 and PD-L1 expression in these myeloid progenitors. In nontumor-bearing mice, PD-1 was detected at very low levels on GMPs (Fig. 2A), whereas PD-L1 was constitutively expressed in CMPs but mostly on GMPs (Fig. 2B). In tumor-bearing mice, PD-L1 was up-regulated in CMPs and GMPs, and its expression levels remained elevated during all assessed time points (Fig. 2, F to J). PD-1 expression was induced on CMPs but more prominently on GMPs (Fig. 2, C to I). Kinetics studies showed that PD-1 expression on GMPs peaked early after tumor inoculation (Fig. 2, C, E, and I), at a time point when tumor growth was not yet measurable. Thus, induction of PD-1 expression in myeloid progenitors is an early event during tumor development.

(A and B) Expression of PD-1 and PD-L1 on CMPs and GMPs of nontumor-bearing mice. (C to J) C57BL/6 mice were inoculated with B16-F10 mouse melanoma, and expression of PD-1 and PD-L1 on CMPs and GMPs was examined on days 9, 12, 14, and 16 after implantation. FACS histograms (C and F) and contour plots (D, E, G, and H) indicating the percentage of positive cells and bar graphs of mean SEM positive cells (I and J) are shown. Results are representative of four independent experiments with six mice per group. (K and L) Kinetics of PD-1 (K) and PD-L1 (L) expression on CMPs (blue) and GMPs (orange) during tumor-driven emergency myelopoiesis. Results are representative of four separate experiments with six mice per group. *P < 0.05, ***P < 0.005, ****P < 0.001.

To determine whether PD-1 expression on GMPs was mediated by growth factors regulating emergency myelopoiesis, we cultured bone marrow cells from nontumor-bearing mice with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony growth factor (GM-CSF), and the TLR4 ligand lipopolysaccharide. PD-1 that was constitutively expressed at low levels in GMPs was up-regulated by culture with each of these factors (fig. S4A), consistent with our findings that PD-1 expression was rapidly induced on GMPs of tumor-bearing mice in vivo (Fig. 2, C, E, and I). Quantitative polymerase chain reaction (qPCR) in purified Linneg bone marrow cells showed that PD-1 mRNA was constitutively expressed in myeloid progenitors and was up-regulated by culture with G-CSF or GM-CSF (fig. S4B). Together, these in vivo and in vitro studies provide evidence that PD-1 expression on myeloid progenitors is regulated by a direct cell-intrinsic effect of factors driving cancer-mediated emergency myelopoiesis.

To examine whether PD-1 was expressed in MDSCs in humans, we used samples from healthy donors and patients with malignant non-Hodgkins lymphoma (NHL) (figs. S5 and S6). A high level of PD-1expressing M-MDSCs was detected in the peripheral blood of three patients with treatment-refractory NHL but not in two patients who responded to treatment or five healthy donors (fig. S6). These results show that PD-1 expression is detected in human MDSCs and serve as a paradigm, suggesting that PD-1 expression in MDSCs of patients with cancer might be a clinically relevant event.

To examine whether PD-1 might have an active role in tumor-induced stress myelopoiesis, we used PD-1deficient (PD-1/) mice. PD-1 deletion, which resulted in decreased tumor growth (Fig. 3, A and B), substantially altered tumor-induced stress myelopoiesis (Fig. 3, C to E). Although accumulation of CMPs was comparable, accumulation of GMPs was significantly diminished in PD-1/ mice (Fig. 3, C and D), indicating that GMPs might be a key target on which PD-1 mediated its effects on myeloid progenitors (Fig. 3E). Kinetics studies showed sustained GMP expansion in wild-type (WT) tumor-bearing mice. In contrast, in PD-1/ tumor-bearing mice, GMPs displayed a rapid expansion and subsequent decline (fig. S7). In parallel, in PD-1/ mice, there was an increase of differentiated CD11b+Ly6Chi monocytic cells not only in the tumor (Fig. 3H) but also in the spleen and the small intestine, which also displayed an increase in CD11c+MHCII+ DCs (Fig. 3, F and G). Moreover, at these sites, there was a significant increase of the CD11b+Ly6C+/CD11b+Ly6G+ ratio (Fig. 3, I to K), indicating a shift of myelopoiesis output toward monocytic lineage dominance. These Ly6Chi monocytes, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs in PD-1/ tumor-bearing mice expressed interferon (IFN) regulatory factor 8 (IRF8), and all myeloid subsets had elevated expression of the retinoic acid receptor-related orphan receptor (RORC or ROR) (Fig. 3, L to N, and fig. S8). Similar results were observed in two additional tumor models, the MC38 colon adenocarcinoma and the MC17-51 fibrosarcoma model (fig. S9), both of which induced cancer-driven emergency myelopoiesis (fig. S3).

(A and B) WT and PD-1/ mice were inoculated with B16-F10 melanoma, and tumor size was monitored daily (A). Mice were euthanized on day 16, and tumor weight was measured (B). Data shown are means SEM of six mice per group and are representative of six independent experiments. (C) Mean percentages SEM of LSK (Linneg, Sca1pos, CD127neg, c-kitpos) and LK (Linneg, Sca1neg, CD127neg, c-kitpos) hematopoietic precursors, CMP, and GMP in the bone marrow of nontumor-bearing and tumor-bearing WT and PD-1/ mice. GMPs in PD-1/ mice were significantly lower compared with GMPs in WT mice (**P < 0.01). (D) Representative contour plots of FACS analysis for CMP and GMP in the bone marrow of tumor-bearing WT and PD-1/ mice. (E) Schematic presentation of myeloid lineage differentiation. The arrowhead indicates GMP, the key target population of PD-1 during emergency myelopoiesis. HSC, hematopoietic stem cells; MPP, multi-potent progenitor; MDP, monocyte/macrophages and DC precursors; CDP, common dendritic cell progenitors; CLP, common lymphoid progenitors. (F to H) Mean percentages of CD45+CD11b+, CD11b+Ly6C+, CD11b+Ly6G+, and CD11c+MHCII+ in the spleen (F), small intestine (G), and B16-F10 site (H) of tumor-bearing WT and PD-1/ mice. (I to K) Representative plots of FACS analysis for CD11b+Ly6Chi and CD11b+Ly6C+/CD11b+Ly6G+ ratio in the spleen (I), small intestine (J), and B16-F10 site (K). (L to N) Mean percentages SEM of RORC and IRF8 expressing CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid cells within the CD45+CD11b+ gate in the spleen (L), small intestine (M), and B16-F10 site (N). Data from one representative experiment of three independent experiments with six mice per group are shown. (O and P) Diminished suppressive activity (O) and NO production (P) of CD11b+Ly6C+ cells isolated from PD-1/ tumor-bearing mice. CD11b+Ly6C+ cells were isolated from tumor-bearing WT and PD-1/ mice and cultured at various ratios with OTI splenocytes stimulated with OVA257264. Data show means SEM of one representative of two experiments (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.001).

IRF8 regulates myeloid cell fate to monocyte/macrophage and DC differentiation versus granulocyte differentiation (22, 23), explaining the increase of CD11b+Ly6C+/CD11b+Ly6G+ ratio that we observed in tumor-bearing PD-1 KO mice. IRF8 is designated as one of the terminal selectors that control the induction and maintenance of the terminally differentiated state of these myeloid cells (22, 23). Moreover, IRF8 shifts the fate of myeloid cells away from immature MDSC, which are characterized by a restriction in IRF8 expression (24, 25). Retinoid-related orphan nuclear receptors not only are required for myelopoiesis and are mediators of the inflammatory response of effector Ly6Chi monocytes and macrophages (21, 26) but also can be expressed by MDSC (21). For these reasons, we examined the functional properties of CD11b+Ly6C+ cells in PD-1/ tumor-bearing mice. A key mechanism by which CD11b+Ly6C+ M-MDSCs mediate suppression of T cell responses involves the production of NO (27). We assessed the immunosuppressive function and found diminished NO production and diminished suppressor capacity of CD11b+Ly6C+ myeloid cells isolated from tumor-bearing PD-1/ mice compared with their counterparts isolated from tumor-bearing WT control mice (Fig. 3, O and P). Thus, PD-1 ablation switches the fate and function of myeloid cells away from immunosuppressive MDSC and promotes the generation of differentiated monocytes, M, and DC. The expansion of CD11b+Ly6Chi monocytes, the increase of the CD11b+Ly6C+/CD11b+Ly6G+ ratio, and the up-regulation of RORC in myeloid cells of the spleen of PD-1/ mice were already observed on day 9 after tumor inoculation, when tumors were not yet measurable, and on day 12, when tumors in WT and PD-1/ mice had comparable size (fig. S10). These results indicate that the effects of PD-1 ablation on the myeloid compartment of PD-1/ tumor-bearing mice preceded the differences in tumor growth.

To determine the potential therapeutic relevance of these findings, we examined whether changes in the myeloid compartment might be detected during treatment with PD-1blocking antibody. Compared with the control treatment group, mice receiving antiPD-1 antibody (fig. S11A) had diminished accumulation of GMP in the bone marrow (fig. S11B) and increased expansion of Ly6C+ monocytes and DC in the tumor site (fig. S11D), with effector features characterized by the expression of RORC, IRF8, and IFN- (fig. S11, E to G and I). In contrast, cells expressing interleukin-4 receptor (IL-4Ra), a marker of MDSC (10, 28), were significantly decreased (fig. S11H). Thus, treatment with antiPD-1blocking antibody promotes the differentiation of myeloid cells with effector features while suppressing expansion of MDSC in tumor-bearing mice.

To determine whether these changes on myeloid cell fate in PD-1/ mice were mediated by myeloid cellintrinsic effects of PD-1 ablation or by the effects of PD-1neg T cells on myeloid cells, we generated mice with conditional targeting of Pdcd1 gene (PD-1f/f) (fig. S12A) and crossed them with mice expressing cre recombinase under the control of the lysozyme (LysM) promoter to induce selective ablation of the Pdcd1 gene in myeloid cells (PD-1f/fLysMcre) or with mice expressing cre recombinase under the control of the CD4 promoter to induce selective ablation of the Pdcd1 gene in T cells (PD-1f/fCD4cre) (fig. S12, B and C). In PD-1f/fLysMcre mice, tumor growth was significantly diminished (Fig. 4, A and B), indicating that despite the preserved PD-1 expression in T cells, myeloid-specific PD-1 ablation in PD-1f/fLysMcre mice was sufficient to inhibit tumor growth. Tumor-driven emergency myelopoiesis was selectively affected in PD-1f/fLysMcre mice. Although myeloid-specific PD-1 ablation resulted in expansion of CMPs, accumulation of GMPs was prevented (Fig. 4C). In contrast, no change on cancer-driven emergency myelopoiesis was detected in PD-1f/fCD4cre mice, which had comparable expansion of CMP and GMP to PD-1f/f control mice (Fig. 5A).

(A and B) PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice were inoculated with B16-F10 melanoma, and tumor size was monitored daily (A). After mice were euthanized, tumor weight was measured (B). (C) Mean percentages SEM of CMP and GMP in the bone marrow of tumor-bearing PD-1f/f and PD-1f/fLysMcre mice. (D) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid subsets in the spleen of tumor-bearing mice. (E) Mean percentages SEM of CD11b+CD45+, CD11b+Ly6C+, and CD11b+Ly6G+ cells and (F) representative contour plots of FACS analysis for CD11b+CD45+ and CD11b+Ly6C+ cells at the tumor site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. (G) Mean percentages SEM of CD16/CD32+, CD86+, CD88+, and CD80+ cells and IFN-expressing myeloid cell subsets within the CD45+CD11b+ gate in B16-F10 tumors from PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. (H) Mean percentages SEM and (I) FACS histograms of IL-4Ra, CD206, and ARG1 expression in CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid cells within the CD11b+CD45+ gate in the spleen of tumor-bearing PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice. Data are from one representative of three independent experiments with six mice per group are shown in all the panels (*P < 0.05, **P < 0.01, ***P < 0.005, and ****P < 0.001).

PD-1f/f and PD-1f/fCD4cre mice were inoculated with B16-F10 melanoma. (A) On day 16, mice were euthanized, and bone marrow CMPs and GMPs were examined by flow cytometry. Mean percentages SEM of CMP or GMP are shown. (B and C) Tumor size was assessed every other day from inoculation (B). On the day of euthanasia, tumor weight was measured (C). (D) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+ and CD11b+Ly6G+ populations within the CD11+CD45+ gate in the spleen. (E) Mean percentages SEM of CD11b+CD45+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ cells within the CD11b+CD45+ gate in the tumor site. (F) Mean percentages SEM of CD16/CD32+, CD86+, CD88+, CD80+, and IFN- expression in the indicated myeloid subsets (CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+) within the CD11b+CD45+ gate in the tumor site. (G to J) Mean percentages SEM of CD4+ and CD8+ TCM and TEM (G), as well as IFN-, IL-2, and IL-17 (H to J) expression in CD4+ and CD8+ TEM and TCM at the tumor site, and respective contour plots (K to M). Results are from one representative of two independent experiments with six mice per group are shown (*P < 0.05 and **P < 0.01).

Myeloid-specific PD-1 ablation in PD-1f/fLysMcre mice not only shifted the differentiation of CD11b+Ly6C+ and CD11b+Ly6G+ myeloid subsets and increased the CD11b+Ly6C+/CD11b+Ly6G+ ratio in the spleen and tumor site as in PD-1/ mice (Fig. 4, D to F) but also resulted in a notably different immunological profile of CD11b+Ly6C+ monocytic myeloid cells, consistent with effector myeloid function as indicated by the expression of effector myeloid cell markers including CD80, CD86, CD16/32 (Fc receptor II/III), and CD88 (C5aR) (Fig. 4G). Consistent with the improved function of myeloid cells, PD-1f/fLysMcre mice also had higher levels of IFN-expressing CD11b+Ly6Chi monocytes and CD11b+F4/80+ Ms (Fig. 4G and fig. S13, A and B) and increase of IRF8+ and RORC+ CD11b+Ly6Chi monocytes (fig. S13, C and D). In contrast, cells expressing IL-4Ra, CD206, and ARG1which are markers of MDSC, immunosuppressive neutrophils, and tolerogenic DCs (2933)were diminished (Fig. 4, H and I). Thus, myeloid-intrinsic PD-1 ablation skews the fate of myeloid cells away from immunosuppressive MDSCs; promotes the differentiation of functional effector monocytes, Ms, and DCs; and has a decisive role in systemic antitumor immunity despite PD-1 expression in T cells.

We studied antitumor responses in mice with T cellspecific PD-1 ablation and found that PD-1f/fCD4cre mice had diminished antitumor protection (Fig. 5, B and C). Consistent with the causative role of myeloid cellspecific PD-1 targeting in the differentiation and function of myeloid cells, T cellspecific PD-1 ablation did not induce expansion of CD11b+CD45+ leukocytes, CD11b+F4/80+ Ms, and CD11c+MHCII+ DCs and increase of CD11b+Ly6C+/CD11b+Ly6G+ ratio (Fig. 5, D and E) or immunological features of functional effector myeloid cells (Fig. 5F) in PD-1f/fCD4cre tumor-bearing mice, compared with control tumor-bearing mice. Moreover, despite PD-1 ablation, tumor-bearing PD-1f/fCD4cre mice did not have quantitative differences in tumor-infiltrating TEM cells compared with control tumor-bearing mice (Fig. 5G) or features of enhanced effector function as determined by assessment of cytokine-producing cells (Fig. 5, H to M).

Similar outcomes to those observed with B16-F10 tumor in the differentiation of myeloid cells toward myeloid effectors versus MDSC were obtained when PD-1f/fLysMcre and PD-1f/fCD4cre mice were inoculated with MC38 colon adenocarcinoma cells (Fig. 6, B to I). Moreover, PD-1f/fLysMcre but not PD-1f/f CD4cre mice inoculated with MC38 had functional differences in tumor-infiltrating TEM and T central memory (TCM) cells compared with control tumor-bearing mice (Fig. 6, J to L). In the context of this highly immunogenic tumor, PD-1 ablation in myeloid cells resulted in complete tumor eradication, whereas mice with PD-1 ablation in T cells showed progressive tumor growth (Fig. 6A). Together, these results suggest that by preventing the differentiation of effector myeloid cells and promoting generation of MDSC, myeloid-specific PD-1 expression has a decisive role on T cell function. Thus, although PD-1 is an inhibitor of T cell responses (2, 34, 35), ablation of PD-1 signaling in myeloid cells is an indispensable requirement for induction of systemic antitumor immunity in vivo.

(A) PD-1f/f, PD-1f/fCD4cre, and PD-1f/fLysMcre mice were inoculated with MC38 colon adenocarcinoma, and tumor size was monitored daily. Mice were euthanized on day 21, and mean percentages SEM of CD45+CD11b+ cells and CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F4/80+, and CD11c+MHCII+ myeloid subsets in the spleen (B) and tumor site (C) were determined. (D) Mean percentages SEM of RORC- and IRF8-expressing CD11b+Ly6C+, CD11b+Ly6G+, CD11b+F/480+, and CD11c+MHCII+ myeloid cells and (E) mean percentages SEM of ARG1, IL-4Ra, CD88, and CD80 cells within the same myeloid subsets in the spleen. (F and G) Representative flow cytometry plots for RORC and IRF8 expression. (H) Mean percentages SEM and (I) representative flow cytometry plots of IFN- and ARG1-expressing CD11b+Ly6C+ and CD11b+Ly6G+ myeloid cells at the tumor site. (J to L) Mean percentages SEM of CD4+ and CD8+ TCM and TEM cells (J) and IFN-expressing CD4+ and CD8+ TEM and TCM at the tumor site (K) and respective contour plots (L). Data are from one representative of three experiments with six mice per group (*P < 0.05, **P < 0.01, and ***P < 0.001).

To further investigate the direct effects of PD-1 on myeloid cell fate in the absence of T cells, we used recombination activating gene 2 (RAG2) KO mice (lacking mature T cells and B cells). Treatment of RAG2 KO tumor-bearing mice with antiPD-1blocking antibody resulted in decreased accumulation of GMPs during tumor-driven emergency myelopoiesis (fig. S14A), myeloid cell expansion in the spleen and tumor site (fig. S14, B and C), and enhanced generation of effector myeloid cells (fig. S14, D to G), providing evidence that blockade of PD-1mediated signals skews myeloid lineage fate to myeloid effector cells in a myeloid cellintrinsic and T cellindependent manner. In RAG2 KO mice treated with antiPD-1 antibody, despite the absence of T cells, a decrease of tumor growth was also observed (fig. S14, H and I), suggesting that ablation of PD-1 signaling promotes myeloid-specific mechanisms that induce tumor suppression, one of which might involve increased phagocytosis (8).

To understand mechanisms that might be responsible for the significant differences of myeloid cell fate commitment induced by myeloid-specific PD-1 targeting, we examined whether PD-1deficient bone marrow myeloid progenitors might have distinct signaling responses to the key hematopoietic growth factors that mediate cancer-driven emergency myelopoiesis, which also induced PD-1 expression in GMP during in vitro culture. To avoid any potential impact of bone marrowresiding PD-1/ T cells or mature myeloid cells on the signaling responses of myeloid progenitors, we used Linneg bone marrow from PD-1f/fLysMcre mice because LysMcre is expressed in CMPs and GMPs (36), allowing us to take advantage of the selective deletion of PD-1 in these myeloid progenitors. PD-1deficient GMPs (fig. S15) had enhanced activation of extracellular signalregulated kinase 1/2 (Erk1/2), mammalian target of rapamycin complex 1 (mTORC1), and signal transducer and activator of transcription 1 (STAT1) in response to G-CSF, a main mediator of emergency myelopoiesis (37, 38). These results are notable because each of these signaling targets has a decisive role in the differentiation and maturation of myeloid cells while preventing the generation of immature immunosuppressive MDSC (3942). These findings indicate that PD-1 might affect the differentiation of myeloid cells by regulating the fine tuning of signaling responses of myeloid progenitors to hematopoietic growth factors that induce myeloid cell differentiation and lineage fate determination during emergency myelopoiesis.

Metabolism has a decisive role in the fate of hematopoietic and myeloid precursors. Stemness and pluripotency are regulated by maintenance of glycolysis (43). Switch from glycolysis to mitochondrial metabolism and activation of oxidative phosphorylation and trichloroacetic acid (TCA) cycle are associated with differentiation (44). This is initiated by glycolysis-mediated mitochondrial biogenesis and epigenetic regulation of gene expression (43). The structural remodeling of the mitochondrial architecture during differentiation is characterized by increased replication of mitochondrial DNA to support production of TCA cycle enzymes and electron transport chain subunits, linking mitochondrial metabolism to differentiation (45).

We examined whether PD-1 ablation, which promoted the differentiation of myeloid cells in response to tumor-mediated emergency myelopoiesis, might affect the metabolic properties of myeloid precursors. Linneg bone marrow myeloid precursors were cultured with the cytokines G-CSF/GM-CSF/IL-6 that drive tumor-mediated emergency myelopoiesis in cocktail (Fig. 7, A and B) or individually (Fig. 7, C and D). Hematopoietic stem cell differentiation was documented by decrease of Linneg, which was more prominent in the cultures of PD-1deficient bone marrow cells, and coincided with increase of CD45+CD11b+ cells (Fig. 7, A and B). Ly6C+ monocytic cells dominated in the PD-1f/fLysMcre cultures, whereas Ly6G+ granulocytes were decreasing compared with PD-1f/f control cultures (Fig. 7, C and D), providing evidence for a cell-intrinsic mechanism of PD-1deficient myeloid precursors for monocytic lineage commitment. Glucose uptake, but more prominently, mitochondrial biogenesis, was elevated in PD-1deficient CMP and GMP (Fig. 7, E and F). Bioenergetics studies showed that PD-1deficient cells developed robust mitochondrial activity (Fig. 7G) and increase of oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio during culture (Fig. 7H), indicating that mitochondrial metabolism progressively dominated over glycolysis. This bioenergetic profile is consistent with metabolism-driven enhanced differentiation of hematopoietic and myeloid precursors (45, 46).

(A and B) Linneg bone marrow from PD-1f/f and PD-1f/fLysMcre mice was cultured with GM-CSF, G-CSF, and IL-6 for the indicated time intervals. Mean percentages SEM of CD11b+CD45+ (A) and Linneg cells (B) are shown. (C and D) Bone marrow cells purified as in (A) and (B) were cultured with the indicated growth factors, and mean percentages SEM of CD11b+Ly6C+ and CD11b+Ly6G+ cells were examined after 48 hours of culture. (E to H) Bone marrow cells were prepared and cultured as in (A) and (B), and at 48 hours of culture, glucose uptake was assessed using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) (E), and mitochondrial biogenesis was assessed by MitoGreen staining and flow cytometry (F). (G) At 24, 48, and 72 hours of culture, OCR and ECAR were measured by a Seahorse extracellular flux analyzer, and mitostress responses at each time point of culture were examined. (H) OCR/ECAR ratio was measured at these time points, and the increase of OCR/ECAR ratio during stimulation was calculated. (I) Linneg bone marrow cells from PD-1f/f and PD-1f/fLysMcre mice were cultured with G-CSF and GM-CSF for 48 hours, and metabolite analysis was performed by mass spectrometry. The unsupervised hierarchical clustering heat map of the top 50 metabolites is shown. (J) At 24, 48, and 72 hours of culture with G-CSF and GM-CSF, mRNA was extracted and analyzed for the expression of the indicated genes by qPCR. Results of the 48-hour culture are shown and are presented as the fold increase over the mRNA level expressed by PD-1f/f cells. Results are from one of three independent experiments. (K to M) At 24 hours of culture with GM-CSF, G-CSF, or IL-6, the content of neutral lipid droplets, including triglycerides and cholesterol esters, was assessed by flow cytometry using boron-dipyrromethene (BODIPY) 493/503. Mean percentages SEM (K) of BODIPY 493/503positive cells within the CD11b+CD45+ gate, representative contour plots (L), and histograms of FACS analysis (M) are shown. (N) PD-1f/f and PD-1f/fLysMcre DC were differentiated in the presence of B16-F10 tumor supernatant, and the content of neutral lipids was assessed. Mean percentage SEM of BODIPY 493/503positive DC within the CD45+CD11b+ gate is shown. Results are representative of three experiments. *P < 0.05, **P < 0.01, and ***P < 0.005.

We performed unbiased global metabolite analysis to determine whether PD-1deficient myeloid precursors developed a distinct metabolic program. Compared with control, PD-1deficient cells had elevated metabolic intermediates of glycolysis and pentose phosphate pathway (PPP), acetylcoenzyme A (coA), and the TCA cycle metabolites citrate and -ketoglutarate, but the most prominent difference was the elevated cholesterol (Fig. 7I, figs. S16 and S17, and table S1). Abundant cytosolic acetyl-coA can be used for fatty acid and cholesterol biosynthesis (fig. S17) (43). Moreover, mTORC1 activates de novo cholesterol synthesis via sterol regulatory element-binding protein 1 (SREBP1), which regulates transcription of enzymes involved in cholesterol synthesis (47, 48). Because acetyl-coA was elevated (Fig. 7I and fig. S17) and mTORC1 activation was enhanced in PD-1deficient myeloid progenitors in response to growth factors driving emergency myelopoiesis (fig. S15), we examined whether activation of the mevalonate pathway that induces cholesterol synthesis (fig. S18A) might be involved. In PD-1deficient myeloid progenitors cultured with growth factors of emergency myelopoiesis, mRNA of genes regulating cholesterol synthesis and uptake was increased, mRNA of genes promoting cholesterol metabolism was decreased (Fig. 7J and fig. S18B), whereas cellular cholesterol and neutral lipid content was elevated (Fig. 7, K to M). PD-1deficient DC not only differentiated in vitro in the presence of B16-F10 tumor supernatant but also had a significant increase of cholesterol and neutral lipids compared with similarly differentiated DC from control mice (Fig. 7N). Consistent with these in vitro findings, glucose uptake and content of cholesterol and neutral lipids were elevated in GMPs of tumor-bearing PD-1 KO mice compared with control mice at days 7 or 9 after tumor inoculation, respectively, when tumors were not yet detectable or tumors in WT and PD-1 mice had equal size (fig. S19). Thus, features associated with metabolism-driven differentiation of myeloid progenitors are enhanced early in tumor-bearing PD-1 KO mice.

In addition to cholesterol synthesis, mevalonate also leads to the synthesis of isoprenoids, including geranylgeranyl pyrophosphate (GGPP) (fig. S17), which is required for protein geranylgeranylation catalyzed by geranylgeranyltransferase and has an active role in the up-regulation of RORC expression (49). Our metabolite analysis showed increased GGPP (Fig. 7I), providing a mechanistic explanation for the up-regulation of RORC in PD-1deficient myeloid cells. Cholesterol accumulation is associated with skewing of hematopoiesis toward myeloid lineage and monocytosis, induces a proinflammatory program in monocytes/macrophages and DC, and amplifies TLR signaling (5052). Together, these results unravel a previously unidentified role of PD-1 targeting in regulating myeloid lineage fate commitment and proinflammatory differentiation of monocytes, macrophages, and DC during tumor-driven emergency myelopoiesis, through metabolic reprogramming.

Previously, it was determined that monocyte/macrophage terminal differentiation is controlled by the combined actions of retinoid receptors and the nuclear receptor peroxisome proliferatoractivated receptor (PPAR), which is regulated by cholesterol and promotes gene expression and lipid metabolic processes, leading to terminal macrophage differentiation (26, 53). Because our in vitro studies showed that PD-1deficient myeloid progenitors developed a distinct metabolic program with elevated cholesterol metabolism, we examined whether PD-1 ablation might alter the expression of PPAR in addition to RORC. We found that the expression of PPAR was elevated in CD11b+Ly6C+ monocytic cells and M isolated from tumors of PD-1/ and PD-1f/fLysMcre mice (Fig. 8, A to C). Because PD-1deficient myeloid progenitors developed robust mitochondrial activity during culture in vitro (Fig. 7, G and H) and PPAR is involved in mitochondrial function (53), we examined whether myeloid cells in tumor-bearing mice have improved mitochondrial metabolism, a feature that has an important role in supporting antitumor function of other immune cells (54). Monocytes, M, and DC isolated from tumor of PD-1/, and PD-1f/fLysMcre mice had increased mitochondrial membrane potential compared with myeloid cells from control tumor-bearing mice, consistent with enhanced mitochondrial metabolism (Fig. 8, D to G).

(A to C) Expression of PPAR in myeloid cells at the B16-F10 site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice was examined by flow cytometry. Mean percentages SEM (A), representative histograms (B), and contour plots (C) of PPAR-expressing CD11b+Ly6C+, CD11b+F4/80+, and CD11c+MHCII+ subsets. (D to G) Mitochondrial metabolic activity of myeloid cells at the B16-F10 tumor site in PD-1f/f, PD-1f/fLysMcre, and PD-1/ mice was examined by assessing mitochondrial membrane potential using MitoRed. Mean fluorescence intensity (MFI) SEM of MitoRedpositive CD11b+Ly6C+, CD11b+F4/80+, and CD11c+MHCII+ subsets within the CD45+CD11b+ gate (D to F) and representative plots of FACS analysis (G) are shown. (H to L) In parallel, expression of IFN-, IL-17A, IL-2, IL-10, RORC, and ICOS in CD8+ TCM and TEM isolated from B16-F10bearing PD-1f/f and PD-1f/fLysMcre mice was assessed by flow cytometry. Representative histograms (H), contour plots (I and K), and mean percentages SEM (J, L, and M) within the CD44hiCD62Lhi gate (for TCM) and CD44hiCD62lo gate (for TEM) cells are shown. Data are from one representative of four independent experiments (*P < 0.05, **P < 0.01, and ***P < 0.005).

We investigated whether these significant immunometabolic changes of myeloid cells, induced by myeloid-specific PD-1 targeting, affected immunological properties of T cells that have key roles in their antitumor function. Compared with control PD-1f/f tumor-bearing mice, PD-1f/fLysMcre tumor-bearing mice had no quantitative differences in CD4+ or CD8+ TEM and TCM cells (fig. S20A) but had significant functional differences. There was an increase of IFN-, IL-17, and IL-10producing CD8+ TEM cells and IL-2producing CD8+ TCM cells (Fig. 8, H to J). Inducible T cell costimulator (ICOS) and lymphocyte-activation gene 3 (Lag3) were elevated in T cells from PD-1f/fLysMcre tumor-bearing mice but cytotoxic T-lymphocyte-associated protein 4 (CTLA4), T cell immunoglobulin and mucin domain 3 (Tim3), CD160, and PD-1/PD-L1 were comparable in T cells from PD-1f/f and PD-1f/fLysMcre tumor-bearing mice (Fig. 8, K to M, and fig. S20B). These findings are significant because IL-17producing T helper cell 17 (TH17)/ T cytotoxic cell 17 (Tc17) cells have enhanced antitumor function and mediate durable tumor growth inhibition (55). Moreover, T cells with a hybrid phenotype producing both IFN- and IL-17 might have superior antitumor properties by combining the enhanced effector function of TH1/Tc1 and the longevity and stemness of TH17/Tc17 cells (56). In our studies, these properties of TEM cells correlated with improved antitumor function in PD-1f/fLysMcre mice.

To examine experimentally whether PD-1deficient myeloid cells differentiated in tumor-bearing mice in vivo have improved capacity of inducing antigen-specific T cell responses, we assessed responses of the same primary CD4+ or CD8+ T cells to antigen-loaded DCs isolated from PD-1/ or control mice bearing B16-F10 tumors (fig. S21A). DCs isolated from the spleen of tumor-bearing WT and PD-1/ mice were pulsed with ovalbumin (OVA) and cocultured with OVA-specific CD4+ or CD8+ T cells from OTI or OTII T cell receptor (TCR)transgenic mice. DCs from tumor-bearing PD-1/ mice had superior ability to induce OTI and OTII T cell proliferation and IFN- expression (fig. S21, B and C). Together, our data provide evidence that myeloid cellintrinsic PD-1 ablation induces potent antitumor immunity by decreasing accumulation of MDSC and promoting proinflammatory and effector monocytic/macrophage and DC differentiation, thereby leading to enhanced effector T cell responses.

Our present studies reveal a previously unidentified role of the PD-1 pathway in regulating lineage fate commitment and function of myeloid cells that arise from tumor-driven emergency myelopoiesis. These outcomes are mediated by myeloid-intrinsic effects of PD-1 ablation, leading to altered signaling and metabolic reprogramming of myeloid progenitors characterized by enhanced differentiation and elevated cholesterol synthesis. Consequently, the accumulation of immature immunosuppressive and tumor-promoting MDSC is diminished, and the output of differentiated, inflammatory effector monocytes, M, and DC is enhanced. These immunometabolic changes of myeloid cells promote the differentiation of TEM cells and systemic antitumor immunity in vivo despite preserved PD-1 expression in T cells.

We found that PD-1deficient myeloid progenitors had enhanced activation of Erk1/2 and mTORC1 in response to G-CSF. These results indicate that Erk1/2 and mTORC1, a downstream mediator of phosphatidylinositol 3-kinase (PI3K)/Akt signaling, which are major targets of PD-1 in T cells (2), are subjected to PD-1mediated inhibition in myeloid cells. These results are revealing because Erk1/2 phosphorylation subverts MDSC-mediated suppression by inducing M-MDSCs differentiation to APC (39). Erk and PI3K regulate glycolysis in response to G-CSF (57). PI3K/Akt/mTORC1 signaling is critical in myeloid lineage commitment. Expression of constitutively active Akt in CD34+ cells induces enhanced monocyte and neutrophil development, whereas a dominant negative Akt has the opposite effect (58). mTORC1 is necessary for the transition of hematopoietic cells from a quiescent state to a prepared alert state in response to injury-induced systemic signals (59), for G-CSFmediated differentiation of myeloid progenitors (40), and for M-CSFmediated monocyte/macrophage generation (41). mTORC1 stimulates translation initiation through phosphorylation of 4E (eIF4E)binding protein 1 (4E-BP1) and ribosomal S6 kinases and has a decisive role in the expression of glucose transporters and enzymes of glycolysis and PPP (47). Consistent with these, our studies showed that PD-1deficient myeloid progenitors had elevated expression of glycolysis and PPP intermediates after culture with emergency cytokines in vitro and enhanced monocytic differentiation in tumor-bearing mice in vivo. Together, our findings indicate that PD-1 might affect the differentiation of myeloid cells by regulating the fine tuning of signaling responses of myeloid progenitors to hematopoietic growth factors that induce myeloid cell differentiation and lineage fate determination during emergency myelopoiesis. Further studies will identify how receptor-proximal signaling events mediated by hematopoietic growth factors are targeted by PD-1 in a manner comparable to PD-1mediated targeting of signaling pathways in T cells (2, 34, 35).

Our metabolite analysis showed that a notable difference of PD-1deficient myeloid progenitors was the increased expression of mevalonate metabolism enzymes and the elevated cholesterol. mTORC1 activates SREBP1, which induces transcription of enzymes involved in fatty acid and cholesterol synthesis (48), thereby leading to glycolysis-regulated activation of the mevalonate pathway. Our signaling studies showing enhanced mTORC1 activation and our metabolic studies showing enhanced mitochondrial metabolism and increased cholesterol content in PD-1deficient myeloid cells provide a mechanistic link between the altered differentiation of PD-1deficient myeloid progenitors and the altered immunophenotypic and functional program of PD-1deficient monocytes, M, and DC in tumor-bearing mice. Cholesterol drives myeloid cell expansion and differentiation of macrophages and DC (50, 51, 60) and promotes antigen-presenting function (61). These properties are consistent with the metabolic profile and the increased cholesterol of PD-1deficient myeloid progenitors; the inflammatory and effector features of differentiated monocytes, M, and DC; and the enhanced T effector cell activation in tumor-bearing mice with myeloid-specific PD-1 ablation that we identified in our studies. By such mechanism, PD-1 might centrally regulate antitumor immunity, independently of the expression of PD-1 and its ligands in the TME. Our studies showed that PD-1 expression on myeloid progenitors is an early event during tumor-mediated emergency myelopoiesis and indicate that PD-1 blockade at early stages of cancer might have a decisive effect on antitumor immunity by preventing MDSC generation from myeloid progenitors and inducing the systemic output of effector myeloid cells that drive antitumor T cell responses.

In addition to its expression in myeloid progenitors, in the bone marrow, we found that PD-1 is expressed in all myeloid subsets including M-MDSC, PMN-MDSC, CD11b+F4/80+ M, and CD11c+MHCII+ DC in the tumor and the spleen of tumor-bearing mice, albeit at different levels. This difference might be related to gradient of tumor-derived factors responsible for PD-1 induction such as G-CSF and GM-CSF that we found to induce PD-1 transcription in myeloid progenitors. This possibility would be consistent with the gradual up-regulation of PD-1 expression in splenic myeloid cells, determined by our kinetics studies, which correlates with tumor growth that might be responsible for the increase of systemic levels of tumor-derived soluble factors that induce PD-1. Other cues of the TME known to mediate the activation step of MDSC (14) might also be responsible for the induction of higher PD-1 expression level in the tumor versus the splenic myeloid cells. Our findings unravel a previously unidentified role of PD-1 in myeloid cell fate commitment during emergency myelopoiesis, a process that is involved not only in antitumor immunity but also in the control of pathogen-induced innate immune responses and sterile inflammation (62).

An additional important finding of our studies is that the nuclear receptors RORC and PPAR are up-regulated in myeloid cells by PD-1 ablation. RORs were initially considered retinoic acid receptors but were subsequently identified as sterol ligands. RORC not only is induced by sterols and isoprenoid intermediates (49) but also serves as the high-affinity receptor of the cholesterol precursor desmosterol (63, 64), a metabolic intermediate of cholesterol synthesis via the mevalonate pathway that regulates inflammatory responses of myeloid cells (52, 60). Desmosterol and as sterol sulfates function as endogenous RORC agonists and induce expression of RORC target genes (63, 64). Our studies showed that, in addition to cholesterol, the mevalonate metabolism product GGPP that has an active role in the up-regulation of RORC expression (49) was elevated in PD-1deficient myeloid cells, providing a mechanistic basis for our finding of the elevated RORC expression. Retinoid receptors and PPAR together regulate monocyte/macrophage terminal differentiation (26). Although initially thought to be involved in proinflammatory macrophage differentiation, it was subsequently understood that PPAR predominantly promotes macrophage-mediated resolution of inflammation by inducing expression of the nuclear receptor liver X receptor and the scavenger receptor CD36, thereby regulating tissue remodeling (65). PPAR also regulates macrophage-mediated tissue remodeling by efferocytosis and production of proresolving cytokines (66), which can suppress cancer growth (67). The combined actions of RORC and PPAR induced by myeloid-specific PD-1 ablation might be involved in the antitumor function by promoting both proinflammatory and tissue remodeling properties of myeloid cells. Future studies will dissect the specific role of each of these nuclear receptors on the antitumor immunity induced by myeloid cellspecific ablation of PD-1.

In conclusion, our results provide multiple levels of evidence that myeloid-specific PD-1 targeting mediates myeloid cellintrinsic effects, which have a decisive role on systemic antitumor responses. This might be a key mechanism by which PD-1 blockade induces antitumor function. Recapitulating this immunometabolic program of myeloid cells will improve the outcome of cancer immunotherapy.

immunology.sciencemag.org/cgi/content/full/5/43/eaay1863/DC1

Materials and Methods

Fig. S1. Gating strategy of hematopoietic and myeloid precursors in the bone marrow.

Fig. S2. Gating strategy of myeloid subsets in the spleen and tumor site.

Fig. S3. Cancer-induced emergency myelopoiesis in three different mouse tumor models.

Fig. S4. PD-1 expression is induced on myeloid progenitors by emergency cytokines.

Fig. S5. Gating strategy for identification of MDSC in human blood samples.

Fig. S6. PD-1 expression in human MDSC.

Fig. S7. PD-1 ablation alters tumor-driven emergency myelopoiesis.

Fig. S8. PD-1 ablation induces expression of RORC and IRF8 in myeloid cells expanding in response to tumor-driven emergency myelopoiesis.

Fig. S9. PD-1 ablation induces expression of RORC and IRF8 in myeloid cells expanding in mice-bearing MC38 or MC17-51 tumors.

Fig. S10. PD-1 ablation increases the output of RORChi effector-like myeloid cells at early stages of tumor growth.

Fig. S11. Therapeutic targeting of PD-1 increases effector features of myeloid cells and decreases tumor growth.

Fig. S12. Myeloid-specific and T cellspecific PD-1 deletion.

Fig. S13. Myeloid-specific PD-1 ablation promotes expansion of IRF8hi and RORChi monocytes and IFN-producing monocytes and macrophages in the tumor site.

Fig. S14. Tumor-induced emergency myelopoiesis and myeloid effector differentiation in Rag2-deficient mice treated with PD-1 antibody.

Fig. S15. PD-1 ablation reduces the threshold of growth factormediated signaling in GMP.

Fig. S16. Myeloid-specific PD-1 ablation induces a distinct metabolic profile characterized by elevated cholesterol.

Fig. S17. Metabolic pathways linking glycolysis to PPP, fatty acid, and cholesterol synthesis.

Fig. S18. Schematic presentation of the mevalonate pathway.

Fig. S19. Increase of glucose uptake and neutral lipid content in PD-1deficient myeloid progenitors early after tumor implantation.

Fig. S20. Myeloid-specific PD-1 deletion alters the immunological profile of CD8+ TEM cells.

Fig. S21. PD-1 ablation enhances antigen presentation ex vivo by tumor-matured DC.

Table S1. List of significantly different metabolites.

Table S2. List of antibodies used for surface staining.

Table S3. List of antibodies used for intracellular staining.

Table S4. List of antibodies used for phenotype of human MDSC.

Table S5. Raw data in Excel spreadsheet.

References (6871)

Acknowledgments: Funding: This work was supported by NIH grants CA183605, CA183605S1, and AI098129-01 and by the DoD grant PC140571. Author contribution: L.S. participated in the conceptualization of the project and experimental design, performed experiments and the analysis and validation of the data, prepared figures, and participated in the preparation of the manuscript. M.A.A.M. performed experiments and the analysis and validation of the data, prepared figures, and participated in the preparation of the manuscript. J.D.W., N.M.T.-O., A.C., R.P., Q.W., and M.Y. participated in various steps of the experimental studies. J.A. participated in the experimental design of metabolite studies and the formal analysis and the validation of the data and participated in the preparation of the manuscript. N.P. participated in the conceptualization of the project, designed and performed the bioenergetics studies, and participated in experiments, the analysis and validation of the data, and the preparation of the manuscript. V.A.B. had the overall responsibility of project conceptualization, experimental design, investigation, data analysis and validation, and preparation of the manuscript and figures. Competing interests: V.A.B. has patents on the PD-1 pathway licensed by Bristol-Myers Squibb, Roche, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, and Dako. The authors declare no other competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials.

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Targeted deletion of PD-1 in myeloid cells induces antitumor immunity - Science

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Researchers at Baylor College of Medicine Discover How to Improve Bone Repair – Gilmore Health News

By daniellenierenberg

Researchers at Baylor College of Medicine have discovered a new mechanism that helps maintain and repair bones in adults. Ultimately, this could help develop new therapeutic strategies to improve bone healing.

Knee Bones

Osteoporosis is a skeletal disease characterized by reduced bone density and changes in the microarchitecture of bones. These changes weaken the bone and increase the risk of fracture. This disease develops particularly in older people. Today, a new study could eventually lead to the development of therapeutic strategies to improve bone healing in these patients. According to the results published in the journal Cell Stem Cell on the 5th December, 2019 researchers have discovered a new mechanism that contributes to the maintenance and repair of bones in adults.

Read Also: HGH Is Now A Solid Treatment For Osteoporosis According To Studies

Adult bone repair relies on the activation of bone stem cells, which still remain poorly characterized. Bone stem cells have been found both in the bone marrow inside the bone and also in the periosteum the outer layer of tissue that envelopes the bone. Previous studies have shown that these two populations of stem cells, although they share many characteristics, also have unique functions and specific regulatory mechanisms. said Dr. Dongsu Park, assistant professor of molecular and human genetics, pathology and immunology at Baylor College of Medicine, where the study was conducted.

Of these two populations, periosteal stem cells are the least known. Although the scientists know that this is a heterogeneous population of cells that can contribute to the thickness, formation and repair of bone fractures, no one has yet been able to distinguish between the different subtypes of bone stem cells in order to study the regulation of their different functions.

Here, however, Dongsu Park and colleagues were able to develop a technique in mice to identify different subpopulations of periosteal stem cells, define their contribution to the repair of bone fractures and identify the specific factors that regulate their migration and proliferation under physiological conditions.

In rats, they discovered specific markers for this class of cells. They identified a specific subset of stem cells that contribute to lifelong bone regeneration in adults. They also observed that periosteal stem cells react to inflammatory molecules, chemokines, which are normally produced in bone injuries.

Read Also: The Exciting Future of Joint and Cartilage Repair

In detail, periosteal stem cells have receptors that bind to the CCL5 chemokine. The CCL5 chemokine sends a signal to the cells to migrate to the injured bone and repair it. By suppressing the CCL5 gene in rats, the researchers found defects in bone repair that delayed healing. However, when they gave CCL5 to rats that had lost CCL5, the bones recovered faster.

Our findings contribute to a better understanding of the healing of adult bones. We believe this is one of the first studies to show that bone stem cells are heterogeneous and that different subtypes have unique properties that are regulated by specific mechanisms, said Dongsu Park. We have identified markers that allow us to distinguish between the subtypes of bone stem cells and have investigated what each subtype contributes to bone health. The understanding of how the functions of bone stem cells are regulated offers the possibility of developing new therapeutic strategies for the treatment of bone damage in adults.

Read Also: Implants from Own Stem Cells May Offer Solution to Back Pain, Researchers Say

In the long term, these findings may therefore have potential therapeutic applications, particularly in people with osteoporosis or diabetes.Indeed, people with diabetes may be prone to falls and fractures due to possible neurological, visual or renal complications. In addition, bone fragility in diabetics is likely to be due to changes in bone remodeling and, in particular, an increase in bone resorption.

https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30458-8?

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Researchers at Baylor College of Medicine Discover How to Improve Bone Repair - Gilmore Health News

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The ‘supercells’ that cured an infant’s grave genetic illness – FRANCE 24

By daniellenierenberg

McLean (United States) (AFP)

When a person's immune system is impaired by a genetic disease, a bone-marrow transplant can be a powerful therapeutic tool, but with a major downside: during the first few months the recipient's defenses against viruses are severely weakened. The slightest infection can lead to a hospital trip.

A still-experimental type of treatment known as T-cell therapy aims to assist during this vulnerable period -- the months during which the body is rebuilding its natural defenses. After two decades of clinical trials, the technology has been refined, and is being used to treat more and more patients, many of them children.

A boy named Johan is one of them.

Today he is a mischievous, smiling toddler with a thick shock of light-brown hair, who never tires, playfully tormenting the family's puppy, Henry.

There is no sign of the three-year-long medical and emotional roller-coaster ride he and his family, who live in an affluent Washington suburb, have been on.

The first traumatic surprise came with the results of a pregnancy test: Johan was not planned.

"That was a huge shock. I cried," said his mother, 39-year-old Maren Chamorro.

- Risky procedure -

She had known since childhood that she carried a gene that can be fatal in a child's first 10 years, chronic granulomatous disease (CGD).

Her brother died of it at the age of seven. The inexorable laws of genetics meant that Maren had a one in four chance of transmitting it to her child.

For their first children, she and her husband Ricardo had chosen in-vitro fertilization, allowing the embryos to be genetically tested before implantation.

Their twins Thomas and Joanna were born -- both disease-free -- seven and a half years ago.

But in Johan's case, a post-birth genetic test quickly confirmed the worst: he had CGD.

After conferring with experts at Children's National Hospital in Washington, the couple took one of the most important decisions of their lives: Johan would receive a bone-marrow transplant, a risky procedure but one that would give him a chance of a cure.

"Obviously, the fact that Maren had lost a sibling at a young age from the disease played a big role," Ricardo confided.

Bone marrow, the spongy tissue inside bones, serves as the body's "factory" for the production of blood cells -- both red and white.

- His brother's immune system -

Johan's white blood cells were incapable of fighting off bacteria and fungal infections. A simple bacterial infection, of negligible concern in a healthy child, could spread out of control in his young body.

Luckily, Johan's brother Thomas, six years old at the time, was a perfect match. In April 2018, doctors first "cleansed" Johan's marrow using chemotherapy. They then took a small amount of marrow from Thomas's hip bones using a long, thin needle.

From that sample they extracted "supercells," as Thomas calls them -- stem cells, which they reinjected into Johan's veins. Those cells would eventually settle in his bone marrow -- and begin producing normal white blood cells.

The second step was preventive cell therapy, under an experimental program led by immunologist Michael Keller at Children's National Hospital.

The part of the immune system that protects against bacteria can be rebuilt in only a matter of weeks; but for viruses, the natural process takes at least three months.

- Hurdles remain -

From Thomas's blood, doctors extracted specialized white blood cells -- T-cells -- that had already encountered six viruses.

Keller grew them for 10 days in an incubator, creating an army of hundreds of millions of those specialized T-cells. The result: a fluffy white substance contained in a small glass vial.

Those T-cells were then injected into Johan's veins, immediately conferring protection against the six viruses.

"He has his brother's immune system," said Keller, an assistant professor at Children's National.

Johan's mother confirmed as much: today, when Thomas and Johan catch a cold, they have the same symptoms, and for nearly the same amount of time.

"I think it's pretty cool to have immunity from your big brother," Maren Chamorro said.

This therapeutic approach -- boosting the body's immune system using cells from a donor or one's own genetically modified cells -- is known as immunotherapy.

Its main use so far has been against cancer, but Keller hopes it will soon become available against viruses for patients, like Johan, who suffer from depressed immune systems.

The chief obstacles to that happening are the complexity of the process and the costs, which can run to many thousands of dollars. These factors currently restrict the procedure to some 30 medical centers in the United States.

For Johan, a year and a half after his bone marrow transplant, everything points to a complete success.

"It's neat to see him processing things, and especially play outside in the mud," his mother said.

"You know, what a gift!"

Her only concern now is the same as any mother would have -- that when her son does fall ill, others in the family might catch the same bug.

2020 AFP

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The 'supercells' that cured an infant's grave genetic illness - FRANCE 24

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Innovative therapies: Novel targets in allergic inflammation – SelectScience

By daniellenierenberg

Meet the inflammation and immunity researcher studying the fundamental cellular mechanisms behind uncontrolled inflammatory responses to allergens

As the prevalence of allergic disease continues to rise worldwide, the work of immunologist Dr. Adam MacNeil has never been more important. By identifying novel targets in allergic inflammation to enable the development of innovative therapies, MacNeil and his team are pushing toward a healthier future. Were interested in allergic inflammation from two different branches, firstly, how the cells that contribute to inflammation emerge from the bone marrow, and secondly, how mature mast cells contribute to inflammatory mechanisms at the site of exposure, explains MacNeil, associate professor in the interdisciplinary Health Sciences department at Brock University, Canada.

Dr. Adam J. MacNeil, Associate Professor of Immunologyat Brock University's Department of Health Sciences.Pictured from left to rightare;Melissa Rouillard, Aindriu Maguire, Rob Crozier, Adam MacNeil, Jeremia Coish, Katie Hunter, Colton Watson, and Natalie Hicks. Image courtesy of theMacNeil Lab.

The MacNeil Lab investigates mechanisms in hematopoietic stem cells directing the maturation of the most well-known allergic mediator cellsmature mast cellsthat drive allergic inflammation. A key research goal for the team is to identify how an allergen activates a mast cell to create an inflammatory response.

Seeking to understand the signals that stimulate a progenitor cell to become a mast cell in different tissues, this research looks to determine the signaling pathways directing the epigenetic, and ultimately proteomic, profile of these cells1-3. To do this, cells are isolated and matured from bone marrow to create functional, phenotypical mast cells, which are primed with allergen-specific IgE molecules before addition of the allergen to activate the cells. The inflammatory response to the allergen, and the cell signaling processes that contribute to the inflammatory mechanisms, can then be measured through the secretion of histamines in degranulation mechanisms, or release of pro-inflammatory mediators such as cytokines, chemokines, and lipid metabolites.

Brock University

Being able to identify and sort cells with a specific immune profile requires tools capable of precision sorting of heterogeneous populations of cells. MacNeil expands: Were working with a heterogeneous population of cells in the bone marrow and trying to take only the stem cells out. So, it's a very small population within the total population of cells. Many of the assays that we want to do with that small population of cells are very well-suited to being sorted directly onto a 96-well plate where we can then actually conduct the experiment directly, knowing exactly how many cells are in each well and what the particular profile of those cells is. That makes the Sony SH800S a really strong tool for our lab.

When it comes to optimizing and streamlining the lab's work, Sony technology offers advantages over traditional methods. The traditional flow cytometer or cell sorter in any core lab is operated by a technician, and they're the only one allowed to touch it. That doesn't make for great learning opportunities for graduate students, and it's much better if they can actually interface with the instrument themselves, says MacNeil. The software and automation really allow for that to happen, but also adds to the robustness of the instrument. The way in which it has been designed means that it's pretty difficult to break it.

With an epigenetic approach to understanding how mast cells differentiate, and the effect of inhibiting specific signaling pathways in those cells, the MacNeil Lab uses sorted cells in functional assays such as immune cell profiling and cytokine secretion. Also, the cells can be sorted into plate-based assays for ChIP or RNA-Seq to assess their genetic profile. We're not only interested in sorting. We bought the device because it's robustly dynamic, explains MacNeil, referring to the Sony SH800S. You can look at data acquisition and not have to even use the sorting function at all in certain scenarios. There are many times that were simply interested in looking at the phenotype of our cells and not worried about sorting necessarily. Weve found this instrument to be very easy to use and to give us robust data in terms of the immune profile of our cells.

In addition, the SH800S microfluidic sorting chip helps to automate key stages of instrument setup and demonstrates versatility with a wide range of chip sizes, ranging from 70130 m, for sorting a variety of cells. The chip ultimately gets to the robustness of the instrument, explains MacNeil. Because of the chip, we have such peace of mind about how the instrument functions that we don't even worry about clogging of the instrument and all of the problems that the chip ultimately solves. If we do run into a problem, we can just change the chip. I certainly find the chip technology to be really well suited to our type of lab environment.

For MacNeil, the Sony SH800S Cell Sorter is a great fit for the lab, with a seamless software interface and great overall instrument design and modularity for easy plate-based sorting.MacNeil lab logocourtesy of the MacNeil Lab.

Working within the diverse multidisciplinary department at Brock University opens unique and fascinating research avenues not available to all immunologists and has led MacNeil to interesting collaborations and knowledge exchange on transdisciplinary projects.

As part of these broader research avenues, working with sociologist Prof. Terrance Wade and cardiovascular biologist Prof. Deborah OLeary, MacNeil also studies adverse experiences in childhood. The team is investigating whether such events may set the immunological stage for dysregulated inflammation in later life, through mechanisms involving stress-stimulated cortisol release that can shape how the immune system is responding4.

In another stream of collaborative immunological research, MacNeil collaborates with psychologist Prof. Anthony Bogaert to look at the role of the immune system in shaping sexual orientation as part of the fraternal birth order effect. This research looks at how early pregnancies stimulate the immune system to make antibodies against brain proteins in fetal males that may then affect their social behaviors in later life5. Its something I may not have expected to ever work on, says MacNeil. But when you come to a diverse department with a wide lens on health, these kinds of opportunities emerge. Were now interested in using the SH800S to test hypotheses for particular mechanisms underlying this phenomenon.

Looking ahead, MacNeil expects tissue heterogeneity to be a key issue to tackle in the field of immunology. Cell populations simply aren't uniform, he says. Mast cells in different locations in the body don't have exactly the same phenotype, and so, as our research proceeds and we continue to probe the role of the mast cell in allergic inflammation, we're very conscious that tissue heterogeneity is going to be a factor. But with such challenges come opportunities. Were ultimately interested in going into those tissues and trying to pull mast cells out. To do this, we would require an instrument like a cell sorter. Once the cells are sorted, we can interrogate their functional phenotype, including how they degranulate, secrete cytokines and metabolize lipids etc. toward one day potentially modulating their phenotype for the hundreds of millions affected by this inappropriate immune response, MacNeil concludes.

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Gene Therapies Make it to Clinical Trials – Discover Magazine

By daniellenierenberg

After years of ethical debates and breakthroughs in the lab, CRISPR has finally made its way to clinical trials. Researchers are now looking at whether the DNA-editing tool, as well as more conventional gene therapies, can effectively treat a wide array of heritable disorders and even cancers.

Theres been a convergence of the science getting better, the manufacturing getting much better, and money being available for these kinds of studies, says Cynthia Dunbar, a senior investigator at the National Heart, Lung, and Blood Institute. Its truly come of age.

CRISPR formally known as CRISPR-Cas9 has been touted as an improvement over conventional gene therapy because of its potential precision. CRISPR (clustered regularly interspaced short palindromic repeats) is a genetic code that, contained in a strand of RNA and paired with the enzyme Cas9, acts like molecular scissors that can target and snip out specific genes. Add a template for a healthy gene, and CRISPRs cut can allow the cell to replace a defective gene with a healthy one.

In April, scientists at the University of Pennsylvania announced they had begun using CRISPR for cancer treatments. The first two patients one with multiple myeloma, the other with sarcoma had cells from their immune systems removed. Researchers used CRISPR to genetically edit the cells in the lab, and then returned them back into their bodies.

On the other side of the country, Mark Walters, a blood and bone marrow transplant specialist at the University of California, San Francisco, Benioff Childrens Hospital in Oakland, is gearing up for trials that will use CRISPR to repair the defective gene that causes sickle cell disease. With CRISPR, once youve made that type of correction, [that cell] is 100 percent healthy, says Walters.

Another team is tackling the same disease using a type of hemoglobin, a protein in red blood cells, thats normally made only in fetuses and newborn babies. Researchers found that some adults continue to produce these proteins throughout their lives, and when those adults also have sickle cell disease, their symptoms are mild. So the international team used CRISPR to disable the gene that interferes with production of this hemoglobin, resuming its production and protecting the adult patients against sickle cell disease.

Several other CRISPR studies are in the works to treat a range of inherited disorders, including hemophilia and SCID-X1 (also known as X-linked severe combined immunodeficiency, the so-called bubble boy disease in which babies are born without a functioning immune system).

At St. Jude Childrens Research Hospital, a gene therapy trial cured Gael Jesus Pino Alva (pictured with his mother, Giannina) of SCID-X1, the bubble boy disease. (Credit: St. Jude Children's Research Hospital/Peter Barta)

The past year also saw success in a handful of experiments on conventional gene therapy. Instead of using CRISPR to repair disease-causing genes, these treatments use hollowed-out viruses to ferry healthy versions of genes into cells. Millions of these altered cells are released into the bloodstream or bone marrow in hopes that enough will land in the right places. But because scientists cant predict where the circulating genes may end up, this shotgun approach has had unintended, sometimes fatal, consequences including, in an earlier study, inadvertently activating leukemia-causing genes in patients treated for SCID-X1.

But in 2019, researchers learned that using a different type of virus one related to HIV to transport the genes may prevent these side effects. In an April study, researchers at St. Jude Childrens Research Hospital in Memphis, Tennessee, and UCSF Benioff Childrens Hospital in Oakland collected bone marrow from eight newborns with SCID-X1. They loaded corrective genes into the disabled HIV-related virus, which carried them into the patients bone marrow stem cells. The infants also received low doses of busulfan, a chemotherapy that gave the doctored stem cells room to grow. So far, we havent seen anything worrisome, says Ewelina Mamcarz, a pediatric oncologist at St. Jude who led the research team. The study recently added its 12th patient.

Gene therapy does have its momentum [back], says Mamcarz, reflecting on the fields setback after the earlier studys leukemia side effects. Theres so much that still needs to be done, and so many questions, she says. [But] this is how medicine evolves. We always want to be better than we were a week ago.

In the future, the hope is that gene therapy technologies will move beyond mending simple genetic mistakes and be used to combat big killers like diabetes or heart disease. [Those diseases are] more challenging, but a lot of them would benefit from knocking out a bad gene, says Dunbar.

For now, though, researchers are optimistic about the progress thats already been made. All of this has been very encouraging, says Dunbar. [And] for sickle cell in the U.S. and hemophilia in the developed world, these diseases may soon be solved.

[This story originally appeared in print as "Gene Therapy Gets Clinical."]

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Gene Therapies Make it to Clinical Trials - Discover Magazine

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