Electric organoid: Neurons derived from people with 22q11.2 syndrome are hyperexcitable and show calcium-signaling deficits.

Courtesy of Pasca lab

Neurons derived from people with 22q11.2 deletion syndrome, a genetic condition linked to autism, show deficits in electrical activity and calcium signaling, according to a new study1. A single gene appears to be largely responsible for these defects, the study shows.

Up to 20 percent of people who lack part or all of the chromosomal region 22q11.2 have autism. Individuals with the deletion may also have schizophrenia, seizures, heart defects, immune dysfunction or learning problems.

The new findings uncover factors that may contribute to the development of psychiatric conditions associated with 22q11.2 deletion syndrome. They could also help researchers identify new therapeutic targets, says lead author Sergiu Pasca, associate professor of psychiatry and behavioral sciences at Stanford University in California.

The syndrome is relatively common, occurring in up to 1 in 4,000 newborns, Pasca says. But researchers do not fully understand how genes in the 22q11.2 region contribute to autism or other conditions, he adds.

To solve this molecular puzzle, Pasca and his team reprogrammed skin cells from 15 people with the deletion and 15 controls into induced pluripotent stem cells. Using a technique they developed in 2015, they coaxed these cells to turn into neurons, which self-organize in a dish into spherical clusters called organoids. The organoids show some key features of the developing cerebral cortex, a brain region implicated in autism.

The neurons derived from people with 22q11.2 syndrome spontaneously fire four times as frequently as neurons derived from controls, the researchers found. And the electrical activity of the 22q cells does not set off the usual spike in calcium levels, which is crucial for neurons to exchange messages.

In some other syndromes tied to schizophrenia and autism, calcium-channel genes are mutated. But the number of channels and the speed at which they work in 22q neurons is the same as in control neurons. Instead, the 22q cells show an unusually low voltage difference across the cell membrane when they arent firing, causing the signaling defects and hyperexcitability, the researchers found.

The researchers suspected that a gene called DGCR8 might be responsible for the neuronal deficits in the organoids because it lies within 22q11.2 and is linked to abnormal electrical activity in the neurons of mice2. DGCR8 is essential for the synthesis of short RNA fragments, called microRNAs, that regulate gene expression.

Lowering DGCR8s expression levels in control neurons reproduced the abnormalities seen in 22q neurons. In contrast, boosting the genes activity in 22q neurons or treating them with antipsychotic drugs prevented them from being overly excitable and reversed their calcium-signaling defects. The study was published 28 September in Nature Medicine.

Previous studies have analyzed lab-grown neurons derived from people with schizophrenia or autism-related disorders such as Rett and fragile X syndromes. But most used only a few human-derived cell lines, says Guo-li Ming, professor of neuroscience at the University of Pennsylvania in Philadelphia. The new study, Ming says, has a total of 30 human lines thats a huge effort.

By studying brain organoids derived from so many people, the researchers were able to identify the gene that might be involved in the psychiatric conditions associated with 22q11.2 syndrome, says Sally Temple, scientific director of the Neural Stem Cell Institute in Rensselaer, New York. Whenever we have a light shining ahead, saying, This is what you should really be looking at, it means that were making progress, she says.

The study participants with 22q11.2 syndrome vary in their psychiatric diagnoses, and yet all the brain organoids derived from their cells show the same neuronal abnormalities. Thats somewhat surprising, because we know there are a lot of differences in the genetic background of different people, Ming says.

The deletion might conspire with other factors to ultimately determine which psychiatric conditions a person has, Pasca says. It could be that the deletion causes cellular defects, and once there is a stressor such as social stress, disease develops. Its also unclear whether these cellular defects are related to the high prevalence of seizures in people with 22q11.2 syndrome, he says.

The hallmarks of most neuropsychiatric conditions can change over time, says Giuseppe Testa, director of the stem cell epigenetics unit at the European Institute of Oncology in Milan, Italy. Studies that look at a larger number of people with 22q11.2 deletion syndrome or other neurodevelopmental conditions could help to elucidate the relationship between the neuronal defects observed in the lab and the psychiatric manifestations of the conditions, Testa says. The new study, however, is a great resource for understanding how the 22q11.2 deletion contributes to schizophrenia and autism, he says.

Pascas team is trying to pinpoint molecules that could open new therapeutic avenues for 22q11.2 deletion syndrome. The antipsychotics they tested restore the unusual voltage differences in the 22q neurons, but they dont address the core mechanisms responsible for psychiatric conditions linked to the syndrome, Pasca says.

Whats more, antipsychotics have many side effects, and not all individuals respond to them, he says. We need better therapies we need to identify what the key molecular players are and target those.

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Brain organoids reveal neuronal flaws in syndrome tied to autism - Spectrum

The biotech industry has been soaring this year, with the SPDR S&P Biotech ETF (XBI) up 26.6% year to date so far. The race for a COVID vaccine has primarily driven this performance, but what if there was another segment of the biotech industry that top hedge fund managers are all going after right now? While many managers are known to take risks, its certainly worth looking into if there is a consensus between them.

The AlphaClone Alternative Alpha ETF (ALFA) tracks an index of equity securities that hedge funds have significant exposure to. The ETFs top three holdings are all biotech firms working on cancer drugs. While many investors have their attention on biotech and pharmaceutical companies working on a COVID vaccine, big money has been focused on the next big thing in biotech, the future oncology drug boom.

Cancer is the second leading cause of death in the U.S. behind heart disease. Almost everyone knows someone that has been affected by one of the many vicious types of cancer. There are now numerous companies focused on ways to treat and cure the various forms. While COVID is at the forefront, cancer is a long-term play. There is even an ETF that covers the cancer industry, the Loncar Cancer Immunotherapy ETF (CNCR), which is up over 39% over the last six months.

As the oncology drug market is expected to reach $394 billion by 2027, here are the three top cancer stocks based on a consensus of hedge fund managers: Seattle Genetics (SGEN), Fate Therapeutics (FATE), and Blueprint Medicines (BPMC).

Seattle Genetics (SGEN)

SGEN is a biotech firm focused on developing antibody-drug conjugates. Its lead lymphoma drug, Adcetris, has been performing quite well since it launched, and it is the primary growth driver for the company. The drugs label was also expanded, providing more revenue for the company. SGEN has been collaborating with Takeda (OTCMKTS:TKPHF), a Japanese pharmaceutical company, for the global development and commercialization of Adcetris.

In addition to Adcetris, the company has a promising pipeline of drug candidates for its antibody-drug conjugate (ADC) technology. In December, the FDA granted accelerated approval to Padcev to treat patients with metastatic bladder cancer, who were previously treated with a checkpoint inhibitor and platinum-based chemotherapy. This drug was created in collaboration with Astellas Pharma (OTCMKTS:ALPMF), another pharmaceutical company.

In April, the FDA approved Tukysa for the treatment of metastatic HER2-positive breast cancer. Investors should also be happy with the news Merck (MRK) plans to buy a 2.9% stake in SGEN. The companies are co-developing and selling SGENs breast cancer therapy, ladiratuzumab vedotin.

The company is rated a Strong Buy in our POWR Ratings system, with a grade of A in Trade Grade, Buy & Hold Grade, and Peer Grade. Those are three out of the four components that make up the POWR Ratings. The stock is also ranked #2 out of 377 Biotech stocks.

Fate Therapeutics (FATE)

FATE is a clinical-stage biopharmaceutical company engaged in the development of programmed cellular immunotherapies for cancer and immune disorders. The company has been building up its pipeline of immuno-oncology product candidates. These treatments are designed to elicit an immune response in patients with cancer.

The companys progress with FT596 is encouraging. FT596 is cell cancer immunotherapy derived from its iPSC line. The induced pluripotent stem cell (iPSC) platform provides a competitive advantage for the company as iPSC cells are stem cells that can become almost any cell type. They are grown from the same cell instead of a patients donated cells. This means that one engineered cell line can be manufactured for many patients, creating what is known as off the shelf immunotherapy.

If the development of this type of therapy is successful, this would reduce the cost of manufacturing and provide a potential cash cow for the company. FATE has entered into collaborations with other companies for fund and research expertise. It is currently working with Ono Pharmaceutical (OTCMKTS:OPHLY) for two off-the-shelf iPSC-derived CAR T-cell product candidates, and Janssen Biotech develop iPSC-derived CAR NK and CAR T-cell product candidates.

FATE is rated a Strong Buy in our POWR Ratings system. It holds a grade of A in Trade Grade, Buy & Hold Grade, and Peer Grade. It is also ranked #24 out of 377 stocks in the Biotech industry. The stock is up a whopping 145.3% after finishing the day up 6.7%.

Blueprint Medicines (BPMC)

BPMC is a biopharmaceutical company focused on improving patients lives with diseases driven by abnormal kinase activation. The company has developed a small molecule drug pipeline in cancer. The firms lead product, Ayvakit, was approved by the FDA in January to treat metastatic gastrointestinal stromal tumor. The drug generated $5.7 million in the second quarter, so its off to a good start.

The company is also looking to expand its label as it is being studied for advanced and smoldering forms of systemic mastocytosis, a condition where certain immune cells, called mast cells, build up under the skin and, or in the bones, intestines, and other organs. If approved for other labels, that should help drive further growth.

Last month, the FDA approved the companys second drug, Gavreto, for the treatment of RET fusion-positive NSCLC or non-small lung cancer. BPMC worked on the drug with Roche (OTCMKTS:RHHBY). Lung cancer is responsible for more cancer deaths than any other in men and women. If Gavreto can become a standard treatment, it could become a goldmine for the company. The drug can also treat medullary thyroid cancers.

BPMC is rated a Strong Buy in our POWR Ratings system. It has grades of A in Trade Grade, Buy & Hold Grade, and Peer Grade. It is also the #9 ranked stock in the Biotech industry. The stock is up over 27% for the past three months and 8.5% over the past week.

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SGEN shares were unchanged in after-hours trading Friday. Year-to-date, SGEN has gained 75.72%, versus a 9.31% rise in the benchmark S&P 500 index during the same period.

David Cohne has 20 years of experience as an investment analyst and writer. Prior to StockNews, David spent eleven years as a Consultant providing outsourced investment research and content to financial services companies, hedge funds, and online publications. David enjoys researching and writing about stocks and the markets. He takes a fundamental quantitative approach in evaluating stocks for readers. More...

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SGEN: The 3 Top Biotech Stocks That Hedge Fund Managers LOVE - StockNews.com

CRANFORD, N.J., Oct. 7, 2020 /PRNewswire/ -- Citius Pharmaceuticals, Inc. ("Citius" or the "Company") (Nasdaq: CTXR), a specialty pharmaceutical company developing and commercializing critical care drug products, announced that it has signed an exclusive agreement with Novellus Therapeutics Limited ("Novellus") to license iPSC-derived mesenchymal stem cells (iMSCs), and has created a new subsidiary, NoveCite, that will be focused on developing cellular therapies.

NoveCite has a worldwide exclusive license from Novellus, an engineered cellular medicines company, to develop and commercialize NoveCite mesenchymal stem cells ("NC-iMSCs") to treat acute respiratory conditions with a near term focus on Acute Respiratory Distress Syndrome ("ARDS") associated with COVID-19. Several cell therapy companies using donor-derived MSC therapies in treating ARDS have demonstrated that MSCs reduce inflammation, enhance clearance of pathogens and stimulate tissue repair in the lungs. Almost all these positive results are from early clinical trials or under the emergency authorization program.

NC-iMSCs are the next generation mesenchymal stem cell therapy. They are believed to be differentiated and superior to donor-derived MSCs. Human donor-derived MSCs are sourced from human bone marrow, adipose tissue, placenta, umbilical tissue, etc. and have significant challenges (e.g., variable donor and tissue sources, limited supply, low potency, inefficient and expensive manufacturing). iMSCs overcome these challenges because they:

Globally, there are 3 million cases of ARDS every year out of which approximately 200,000 cases are in the United States. The COVID-19 pandemic has added significantly to the number of ARDS cases. Once the COVID patients advance to ARDS, they are put on mechanical ventilators. Death rate among patients on ventilators can be as high as 50% depending on associated co-morbidities. There are no approved treatments for ARDS, and the current standard of care only attempts to provide symptomatic relief.

"NoveCite iMSCs have the potential to be a breakthrough in the field of cellular therapy for acute respiratory conditions because of the high potency seen in Novellus' pre-clinical studies, and because iMSCs are iPSC-derived, and therefore overcome the manufacturing challenges associated with donor derived cells," said Myron Holubiak, Chief Executive Officer of Citius.

"We are excited to be part of this effort because of the promise to save lives and reduce long term sequelae in patients with devastating respiratory diseases such as ARDS caused by COVID-19," said Dr. Matthew Angel, Chief Science Officer of Novellus. "Our iMSC technology has multimodal immunomodulatory mechanisms of action that make it potentially promising therapy to treat acute respiratory diseases."

About Citius Pharmaceuticals, Inc.

Citius is a late-stage specialty pharmaceutical company dedicated to the development and commercialization of critical care products, with a focus on anti-infectives and cancer care. For more information, please visit http://www.citiuspharma.com.

About Novellus, Therapeutics, Limited

Novellus is a pre-clinical stage biotechnology company developing engineered cellular medicines using its patented non-immunogenic mRNA high specificity gene editing, mutation-free & footprint-free cell reprogramming and serum insensitive mRNA lipid delivery technologies. Novellus is privately held and is headquartered in Cambridge, MA. For more information, please visit http://www.novellus-inc.com.

About NoveCite iMSC (NC-iMSC)

NoveCite's mesenchymal stem cell therapy product is derived from a human induced pluripotent stem cell (iPSC) line generated using a proprietary mRNA-based (non-viral) reprogramming process. The NC-iMSCs produced from this clonal technique are differentiated from human donor-derived MSCs (bone marrow, placenta, umbilical cord, adipose tissue, or dental pulp) by providing genetic homogeneity. In in-vitro studies, NC-iMSCs exhibit superior potency and high cell viability. NC-iMSCs secrete immunomodulatory proteins that may reduce or prevent pulmonary symptoms associated with acute respiratory distress syndrome (ARDS) in patients with COVID-19. NC-iMSC is an allogeneic (unrelated donor) mesenchymal stem-cell product manufactured by expanding material from a master cell bank.

First generation (human donor-derived) MSCs are isolated from donated tissue followed by "culture expansion". Since only a relatively small number of cells are isolated from each donation, first generation MSCs are increased by growing the cells in culture. Unfortunately, these type of MSCs start to lose potency, and ultimately become senescent. Each donation produces a limited number of MSCs, so a continuous supply of new donors is needed to produce commercial scale. The number and quality of MSCs that can be isolated from different donors can vary substantially.

About Acute Respiratory Distress Syndrome (ARDS)

ARDS is an inflammatory process leading to build-up of fluid in the lungs and respiratory failure. It can occur due to infection, trauma and inhalation of noxious substances. ARDS accounts for approximately 10% of all ICU admissions and almost 25% of patients requiring mechanical ventilation. Survivors of ARDS are often left with severe long-term illness and disability. ARDS is a frequent complication of patients with COVID-19. ARDS is sometimes initially diagnosed as pneumonia or pulmonary edema (fluid in the lungs from heart disease). Symptoms of ARDS include shortness of breath, rapid breathing and heart rate, chest pain (particularly while inhaling), and bluish skin coloration. Among those who survive ARDS, a decreased quality of life is relatively common.

Safe Harbor

This press release may contain "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Such statements are made based on our expectations and beliefs concerning future events impacting Citius. You can identify these statements by the fact that they use words such as "will," "anticipate," "estimate," "expect," "should," and "may" and other words and terms of similar meaning or use of future dates. Forward-looking statements are based on management's current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock price. Factors that could cause actual results to differ materially from those currently anticipated are: the risks associated with developing the NoveCite technology as a treatment for ARDS; risks associated with developing any of our product candidates, including any licensed from Novellus, Inc., including that preclinical results may not be predictive of clinical results and our ability to file an IND for such candidates; our need for substantial additional funds; the estimated markets for our product candidates, including those for ARDS, and the acceptance thereof by any market; risks relating to the results of research and development activities; uncertainties relating to preclinical and clinical testing; the early stage of products under development, including the NoveCite technology; our ability to obtain, perform under and maintain licensing, financing and strategic agreements and relationships; our ability to attract, integrate, and retain key personnel; risks related to our growth strategy; our ability to identify, acquire, close and integrate product candidates and companies successfully and on a timely basis; government regulation; patent and intellectual property matters; competition; as well as other risks described in our SEC filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law.

Contact:Andrew ScottVice President, Corporate Development(O) 908-967-6677 x105(M) 646-522-8410ascott@citiuspharma.com

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SOURCE Citius Pharmaceuticals, Inc.

Company Codes: NASDAQ-SMALL:CTXR

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Citius Pharmaceuticals Signs an Exclusive Worldwide Licensing Agreement with Novellus Therapeutics for Unique iMSC-Therapy for Acute Inflammatory...

MINNEAPOLIS, Oct. 6, 2020 /PRNewswire/ --The National Marrow Donor Program (NMDP)/Be The Match today announced a collaboration with the Minnesota health system M Health Fairview and Marcus Center for Cellular Cures (MC3)/Carolinas Cord Blood Bank at Duke University (Duke) to offer cryopreservation services to transplant centers through the Be The Match BioBank. The collaboration brings together industry-leading expertise in cryopreservation and storage of patient-directed donor blood stem cell products to improve donor availability, collection quality, and ultimately, to provide a more reliable path to transplant for patients.

Through the Be The Match BioBank, blood stem cell donors will be able to donate bone marrow or peripheral blood stem cells (PBSC) for an intended patient on a timeline that is convenient for the donor. The cells are then cryopreserved and stored for the transplant center at no cost to them and shipped to coincide with initiation of the patient's conditioning regimen and optimal treatment timeline.

"We're excited to expand our partnership with Duke University by adding the expertise of physicians and researchers at M Health Fairview University of Minnesota Medical Center to continue to overcome logistical barriers to blood and marrow transplantation that might otherwise disrupt optimal patient care. Through the flexibility offered by the Be The Match BioBank, we believe we can provide transplant centers with a well-matched, available donor more often, and allow the transplant to occur at the best time for the patient," explained Steven Devine, MD, Chief Medical Officer, NMDP/Be The Match, and Associate Scientific Director, CIBMTR (Center for International Blood and Marrow Transplant Research). "The team at the Duke University lab was instrumental in the development of the Be The Match BioBank, as well as supporting donor product cryopreservation during the COVID-19 pandemic to ensure patients can continue to receive the transplants they need."

"We are proud to extend our partnership with the NMDP/Be The Match in a new way. Be The Match BioBank is an innovative way to remove barriers that otherwise may stand in the way of a patient's transplant," said Joanne Kurtzberg, MD, who leads the Marcus Center for Cellular Cures (MC3)/Carolinas Cord Blood Bank at Duke University.

"We are thrilled to be working with the NMDP/Be The Match to offer Be The Match BioBank. Through this partnership, transplant physicians can have confidence a high-quality bone marrow or PBSC product will be available from the donor they requested in the timeframe that works best for their patient," said David McKenna, MD, who leads the Molecular and Cellular Therapeutics program at M Health Fairview.

Be The Match BioBank can be used by any transplant center in the NMDP/Be The Match Network of more than 180 transplant centers worldwide. Blood stem cell donors are informed that the transplant center is requesting cryopreservation and provide consent prior to collection. Donors can also consent to having their donated cells made available to other searching patients in the unlikely event the intended patient is unable to proceed to transplant as planned.

To learn more about Be The Match BioBank, visit Network.BeTheMatchClinical.org/BioBank.

About the National Marrow Donor Program/Be The Match The National Marrow Donor Program/Be The Match is the global leader in providing a cure to patients with life-threatening blood and marrow cancers like leukemia and lymphoma, as well as other diseases. The organization manages the world's largest registry of potential blood stem cell donors and cord blood units. The NMDP/Be The Match partners with a global network to connect patients to their donor match for a transplant, and provides education and support for patients. Through Be The Match BioTherapies, the NMDP/Be The Match partners with cell and gene therapy companies to support the development and delivery of new therapies. The organization conducts research through its research program, CIBMTR (Center for International Blood and Marrow Transplant Research), in collaboration with Medical College of Wisconsin.

About M Health Fairview M Health Fairview is the newly expanded collaboration betweenthe University of Minnesota, University of Minnesota Physicians,and Fairview Health Services. The healthcare system combines the best of academic and community medicine expanding access to world-class, breakthrough care through its 10 hospitals and 60 clinics.

SOURCE Be The Match

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NMDP/Be The Match partners with M Health Fairview and Duke University cryopreservation labs to launch Be The Match BioBank - PRNewswire

DetailsCategory: AntibodiesPublished on Saturday, 03 October 2020 15:56Hits: 667

Opdivo + Yervoy is the first new systemic therapy in over 15 years to be approved by the FDA in this setting1,2

Approval is based on CheckMate -743 in which Opdivo + Yervoy demonstrated superior overall survival vs. standard of care chemotherapy1

Approval marks third indication for Opdivo + Yervoy-based treatments in thoracic cancers and seventh indication overall

PRINCETON, NJ, UA I October 2, 2020 IBristol Myers Squibb (NYSE: BMY) today announced that Opdivo (nivolumab) 360 mg every three weeks plus Yervoy (ipilimumab) 1 mg/kg every six weeks (injections for intravenous use) was approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).1 This approval is based on a pre-specified interim analysis from the Phase 3 CheckMate -743 trial in which Opdivo + Yervoy (n=303) demonstrated superior overall survival (OS) versus the platinum-based standard of care chemotherapy (n=302) (Hazard Ratio [HR]: 0.74 [95% Confidence Interval [CI]: 0.61 to 0.89]; P=0.002), with a median OS (mOS) of 18.1 months (95% CI: 16.8 to 21.5) versus 14.1 months (95% CI: 12.5 to 16.2), respectively.1 These results were observed after 22.1 months of minimum follow-up.3 At two years, 41% of patients treated with Opdivo + Yervoy were alive and 27% with chemotherapy.1,3

Malignant pleural mesothelioma is a rare cancer with limited treatment options. When it is diagnosed in advanced stages, the five-year survival rate is approximately 10 percent, said study investigator Anne S. Tsao, M.D., professor and Section Chief Thoracic Medical Oncology and Director of the Mesothelioma Program at The University of Texas M.D. Anderson Cancer Center.2,4 The survival results from the CheckMate -743 trial show that the combination of nivolumab and ipilimumab could become a new front-line standard of care option. This is exciting news, instilling hope for patients with this devastating disease and for the healthcare providers who care for them.1,3

Opdivo and Yervoy are associated with Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; complications of stem-cell transplant that uses donor stem cells (allogeneic); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when Opdivo is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.1Yervoy is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplant after Yervoy, embryo-fetal toxicity and risks associated when administered in combination with Opdivo.5 Please see the Important Safety Information section below.

This is the third indication for an Opdivo + Yervoy-based combination in the first-line treatment of a form of thoracic cancer.1Opdivo + Yervoy is approved by the FDA as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L11% as determined by an FDA-approved test, and without EGFR or ALK genomic tumor aberrations.1 It is also approved in combination with limited chemotherapy for the first-line treatment of adult patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations regardless of PD-L1 expression.1

Thoracic cancers can be complex and difficult to treat, and we are focused on developing immunotherapy options that may have the potential to extend patients lives, said Adam Lenkowsky, general manager and head, U.S., Oncology, Immunology, Cardiovascular, Bristol Myers Squibb.2,6 Just a few months ago, Opdivo + Yervoy-based combinations received two first-line indications for certain patients with non-small cell lung cancer. Now, Opdivo + Yervoy is approved for use in another type of thoracic cancer, previously untreated unresectable MPM. With todays announcement, Opdivo + Yervoy becomes the first new systemic therapy approved in more than 15 years in this setting, and may offer these patients a chance for a longer life. 1

Opdivo + Yervoy is a unique combination of two immune checkpoint inhibitors that features a potentially synergistic mechanism of action, targeting two different checkpoints (PD-1 and CTLA-4) to help destroy tumor cells: Yervoy helps activate and proliferate T cells, while Opdivo helps existing T cells discover the tumor.1,7 Some of the T cells stimulated by Yervoy can become memory T cells, which may allow for a long-term immune response.7,8,9,10,11,12 Targeting of normal cells can also occur and result in immune-mediated adverse reactions, which can be severe and potentially fatal.1 Please see the Important Safety Information section below.

This approval was granted less than six weeks following the submission of a new supplemental Biologics License Application (sBLA), which was reviewed under the FDAs Real-Time Oncology Review (RTOR) pilot program. The RTOR program aims to ensure that safe and effective treatments are available to patients as early as possible.13 The review was also conducted under the FDAs Project Orbis initiative, enabling concurrent review by the health authorities in Australia, Brazil, Canada and Switzerland.

About CheckMate -743

CheckMate -743 is an open-label, multi-center, randomized Phase 3 trial evaluating Opdivo plus Yervoy compared to chemotherapy (pemetrexed and cisplatin or carboplatin) in patients with histologically confirmed unresectable malignant pleural mesothelioma and no prior systemic therapy or palliative radiotherapy within 14 days of initiation of therapy (n=605).1 Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial.1In the trial, 303 patients were randomized to receive Opdivo 3 mg/kg every two weeks and Yervoy 1 mg/kg every six weeks; 302 patients were randomized to receive cisplatin 75 mg/m2 or carboplatin AUC 5 plus pemetrexed 500 mg/m2 in 3-week cycles for six cycles.1 Treatment in both arms continued until disease progression or unacceptable toxicity or, in the Opdivo + Yervoy arm, up to 24 months.1 The primary endpoint of the trial was OS in all randomized patients.1 Additional efficacy outcome measures included progression-free survival (PFS), objective response rate (ORR) and duration of response (DOR), as assessed by BICR utilizing modified RECIST criteria.1

Select Safety Profile from CheckMate -743 Study

Treatment was permanently discontinued for adverse reactions in 23% of patients treated with Opdivo + Yervoy, and 52% had at least one dose withheld for an adverse reaction.1 An additional 4.7% of patients permanently discontinued Yervoy alone due to adverse reactions. Serious adverse reactions occurred in 54% of patients receiving Opdivo + Yervoy.1 The most frequent (2%) serious adverse reactions in patients receiving Opdivo + Yervoy were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism.1 Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis.1 The most common (20%) adverse reactions were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%) and pruritus (21%).1 The median number of doses was 12 for Opdivo and 4 for Yervoy.3

About Malignant Pleural Mesothelioma

Mesothelioma is a rare but aggressive form of cancer that often forms in the lining of the lungs.2,14 There are approximately 3,000 cases diagnosed in the United States each year.14 Malignant pleural mesothelioma is the most common type of the disease.2 It is most frequently caused by exposure to asbestosand diagnosis is often delayed, with the majority of patients presenting with advanced disease.2,15 Prognosis is generally poor: in patients with advanced malignant pleural mesothelioma, median survival is approximately one year and the five-year survival rate is approximately 10%.2

INDICATIONS

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

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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

Bristol Myers Squibb: Advancing Cancer Research

At Bristol Myers Squibb, patients are at the center of everything we do. The goal of our cancer research is to increase patients quality of life, long-term survival and make cure a possibility. We harness our deep scientific experience, cutting-edge technologies and discovery platforms to discover, develop and deliver novel treatments for patients.

Building upon our transformative work and legacy in hematology and Immuno-Oncology that has changed survival expectations for many cancers, our researchers are advancing a deep and diverse pipeline across multiple modalities. In the field of immune cell therapy, this includes registrational CAR T cell agents for numerous diseases, and a growing early-stage pipeline that expands cell and gene therapy targets, and technologies. We are developing cancer treatments directed at key biological pathways using our protein homeostasis platform, a research capability that has been the basis of our approved therapies for multiple myeloma and several promising compounds in early- to mid-stage development. Our scientists are targeting different immune system pathways to address interactions between tumors, the microenvironment and the immune system to further expand upon the progress we have made and help more patients respond to treatment. Combining these approaches is key to delivering potential new options for the treatment of cancer and addressing the growing issue of resistance to immunotherapy. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines a reality for patients.

About Bristol Myers Squibbs Patient Access Support

Bristol Myers Squibb remains committed to providing assistance so that cancer patients who need our medicines can access them and expedite time to therapy.

BMS Access Support, the Bristol Myers Squibb patient access and reimbursement program, is designed to help appropriate patients initiate and maintain access to BMS medicines during their treatment journey. BMS Access Support offers benefit investigation, prior authorization assistance, as well as co-pay assistance for eligible, commercially insured patients. More information about our access and reimbursement support can be obtained by calling BMS Access Supportat 1-800-861-0048 or by visiting http://www.bmsaccesssupport.com.

About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies as single agents and combination regimens for patients with cancer in Japan, South Korea and Taiwan.

About Bristol Myers Squibb

Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as, Celgene, a Bristol Myers Squibb company and Juno Therapeutics, a Bristol Myers Squibb company.

References

SOURCE: Bristol-Myers Squibb

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US Food and Drug Administration Approves Opdivo (nivolumab) + Yervoy (ipilimumab) as the First and Only Immunotherapy Treatment for Previously...

Researchers from Critical Analytics for Manufacturing Personalized-Medicine (CAMP), an interdisciplinary research group at Singapore-MIT Alliance for Research and Technology (SMART), MITs research enterprise in Singapore, have been awarded Intra-CREATE grants from the National Research Foundation (NRF) Singapore to help support research on retinal biometrics for glaucoma progression and neural cell implantation therapy for spinal cord injuries. The grants are part of the NRFs initiative to bring together researchers from Campus for Research Excellence And Technological Enterprise (CREATE) partner institutions, in order to achieve greater impact from collaborative research efforts.

SMART CAMP was formed in 2019 to focus on ways to produce living cells as medicine delivered to humans to treat a range of illnesses and medical conditions, including tissue degenerative diseases, cancer, and autoimmune disorders.

Singapores well-established biopharmaceutical ecosystem brings with it a thriving research ecosystem that is supported by skilled talents and strong manufacturing capabilities. We are excited to collaborate with our partners in Singapore, bringing together an interdisciplinary group of experts from MIT and Singapore, for new research areas at SMART. In addition to our existing research on our three flagship projects, we hope to develop breakthroughs in manufacturing other cell therapy platforms that will enable better medical treatments and outcomes for society, says Krystyn Van Vliet, co-lead principal investigator at SMART CAMP, professor of materials science and engineering, and associate provost at MIT.

Understanding glaucoma progression for better-targeted treatments

Hosted by SMART CAMP, the first research project, Retinal Analytics via Machine learning aiding Physics (RAMP), brings together an interdisciplinary group of ophthalmologists, data scientists, and optical scientists from SMART, Singapore Eye Research Institute (SERI), Agency for Science, Technology and Research (A*STAR), Duke-NUS Medical School, MIT, and National University of Singapore (NUS). The team will seek to establish first principles-founded and statistically confident models of glaucoma progression in patients. Through retinal biomechanics, the models will enable rapid and reliable forecast of the rate and trajectory of glaucoma progression, leading to better-targeted treatments.

Glaucoma, an eye condition often caused by stress-induced damage over time at the optic nerve head, accounts for 5.1 million of the estimated 38 million blind in the world and 40 percent of blindness in Singapore. Currently, health practitioners face challenges forecasting glaucoma progression and its treatment strategies due to the lack of research and technology that accurately establish the relationship between its properties, such as the elasticity of the retina and optic nerve heads, blood flow, intraocular pressure and, ultimately, damage to the optic nerve head.

The research is co-led by George Barbastathis, principal investigator at SMART CAMP and professor of mechanical engineering at MIT, and Aung Tin, executive director at SERI and professor at the Department of Ophthalmology at NUS. The team includes CAMP principal investigators Nicholas Fang, also a professor of mechanical engineering at MIT; Lisa Tucker-Kellogg, assistant professor with the Cancer and Stem Biology program at Duke-NUS; and Hanry Yu, professor of physiology with the Yong Loo Lin School of Medicine, NUS and CAMPs co-lead principal investigator.

We look forward to leveraging the ideas fostered in SMART CAMP to build data analytics and optical imaging capabilities for this pressing medical challenge of glaucoma prediction, says Barbastathis.

Cell transplantation to treat irreparable spinal cord injury

Engineering Scaffold-Mediated Neural Cell Therapy for Spinal Cord Injury Treatment (ScaNCellS), the second research project, gathers an interdisciplinary group of engineers, cell biologists, and clinician scientists from SMART, Nanyang Technological University (NTU), NUS, IMCB A*STAR, A*STAR, French National Centre for Scientific Research (CNRS), the University of Cambridge, and MIT. The team will seek to design a combined scaffold and neural cell implantation therapy for spinal cord injury treatment that is safe, efficacious, and reproducible, paving the way forward for similar neural cell therapies for other neurological disorders. The project, an intersection of engineering and health, will achieve its goals through an enhanced biological understanding of the regeneration process of nerve tissue and optimized engineering methods to prepare cells and biomaterials for treatment.

Spinal cord injury (SCI), affecting between 250,000 and 500,000 people yearly, is expected to incur higher societal costs as compared to other common conditions such as dementia, multiple sclerosis, and cerebral palsy. SCI can lead to temporary or permanent changes in spinal cord function, including numbness or paralysis. Currently, even with the best possible treatment, the injury generally results in some incurable impairment.

The research is co-led by Chew Sing Yian, principal investigator at SMART CAMP and associate professor of the School of Chemical and Biomedical Engineering and Lee Kong Chian School of Medicine at NTU, and Laurent David, professor at University of Lyon (France) and leader of the Polymers for Life Sciences group at CNRS Polymer Engineering Laboratory. The team includes CAMP principal investigators Ai Ye from Singapore University of Technology and Design; Jongyoon Han and Zhao Xuanhe, both professors at MIT; as well as Shi-Yan Ng and Jonathan Loh from Institute of Molecular and Cell Biology, A*STAR.

Chew says, Our earlier SMART and NTU scientific collaborations on progenitor cells in the central nervous system are now being extended to cell therapy translation. This helps us address SCI in a new way, and connect to the methods of quality analysis for cells developed in SMART CAMP.

Cell therapy, one of the fastest-growing areas of research, will provide patients with access to more options that will prevent and treat illnesses, some of which are currently incurable. Glaucoma and spinal cord injuries affect many. Our research will seek to plug current gaps and deliver valuable impact to cell therapy research and medical treatments for both conditions. With a good foundation to work on, we will be able to pave the way for future exciting research for further breakthroughs that will benefit the health-care industry and society, says Hanry Yu, co-lead principal investigator at SMART CAMP, professor of physiology with the Yong Loo Lin School of Medicine, NUS, and group leader of the Institute of Bioengineering and Nanotechnology at A*STAR.

The grants for both projects will commence on Oct. 1, with RAMP expected to run until Sept. 30, 2022, and ScaNCellS expected to run until Sept. 30, 2023.

SMART was. established by the MIT in partnership with the NRF in 2007. SMART is the first entity in the CREATE developed by NRF. SMART serves as an intellectual and innovation hub for research interactions between MIT and Singapore, undertaking cutting-edge research projects in areas of interest to both Singapore and MIT. SMART currently comprises an Innovation Centre and five interdisciplinary research groups (IRGs): Antimicrobial Resistance, CAMP, Disruptive and Sustainable Technologies for Agricultural Precision, Future Urban Mobility, and Low Energy Electronic Systems.

CAMP is a SMART IRG launched in June 2019. It focuses on better ways to produce living cells as medicine, or cellular therapies, to provide more patients access to promising and approved therapies. The investigators at CAMP address two key bottlenecks facing the production of a range of potential cell therapies: critical quality attributes (CQA) and process analytic technologies (PAT). Leveraging deep collaborations within Singapore and MIT in the United States, CAMP invents and demonstrates CQA/PAT capabilities from stem to immune cells. Its work addresses ailments ranging from cancer to tissue degeneration, targeting adherent and suspended cells, with and without genetic engineering.

CAMP is the R&D core of a comprehensive national effort on cell therapy manufacturing in Singapore.

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SMART researchers receive Intra-CREATE grant for personalized medicine and cell therapy - MIT News

NEW YORK, Oct. 2, 2020 /PRNewswire/ --BrainStorm-Cell Therapeutics Inc. (NASDAQ: BCLI), a leader in developing innovative autologous cellular therapies for highly debilitating neurodegenerative diseases, announced today that the Company will hold a conference call to update shareholders on financial results for the third quarter ended September 30, 2020, and provide a corporate update, at 8:00 a.m., Eastern Daylight Time (EDT), on October 15, 2020.

BrainStorm's CEO, Chaim Lebovits, will present a corporate update, after which, participant questions will be answered. Joining Mr. Lebovits to answer investment community questions will be Ralph Kern, MD, MHSc, President and Chief Medical Officer, David Setboun, PharmD, MBA, Executive Vice President and Chief Operating Officer, and Preetam Shah, PhD, MBA, Executive Vice President and Chief Financial Officer.

Participants are encouraged to submit their questions prior to the call by sending them to:q@brainstorm-cell.com. Questions should be submitted by5:00 p.m. EDT,Tuesday, October 13, 2020.

Teleconference Details BRAINSTORM CELL THERAPEUTICS 3Q 2020

The investment community may participate in the conference call by dialing the following numbers:

Participant Numbers:

Toll Free: 877-407-9205International: 201-689-8054

Those interested in listening to the conference call live via the internet may do so by visiting the "Investors & Media" page of BrainStorm's website atwww.ir.brainstorm-cell.comand clicking on the conference call link.

Event Link: Webcast URL: https://bit.ly/30pVpNG Webcast Replay Expiration: Friday, October 15, 2021

Those that wish to listen to the replay of the conference call can do so by dialing the numbers below. The replay will be available for 14 days.

Replay Number:

Toll Free: 877-481-4010International: 919-882-2331Replay Passcode: 37811

Teleconference Replay Expiration:

Thursday, October 29, 2020

About NurOwn

NurOwn (autologous MSC-NTF) cells represent a promising investigational therapeutic 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 (NTFs). 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. BrainStorm has fully enrolled a Phase 3 pivotal trial of autologous MSC-NTF cells for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm also recently received acceptance from theU.S. Food and Drug Administration(FDA) to initiate a Phase 2 open-label multicenter trial in progressive multiple sclerosis (MS) and initiated enrollment inMarch 2019.

AboutBrainStorm 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 theU.S. Food and Drug Administration(FDA) and theEuropean Medicines Agency(EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has fully enrolled a Phase 3 pivotal trial in ALS (NCT03280056), investigating repeat-administration of autologous MSC-NTF cells at sixU.S.sites supported by a grant from theCalifornia Institute for Regenerative Medicine(CIRM CLIN2-0989). The pivotal study is intended to support a filing forU.S.FDA approval of autologous MSC-NTF cells in ALS. BrainStorm also recently receivedU.S.FDA clearance to initiate a Phase 2 open-label multicenter trial in progressive multiple sclerosis (MS). The Phase 2 study of autologous MSC-NTF cells in patients with progressive MS (NCT03799718) started enrollment inMarch 2019. For more information, visit the company's website atwww.brainstorm-cell.com.

ContactsInvestor Relations:Corey Davis, Ph.D.LifeSci Advisors, LLCPhone: +1 646-465-1138cdavis@lifesciadvisors.com

Media:Paul TyahlaSmithSolvePhone: + 1.973.713.3768Paul.tyahla@smithsolve.com

View original content:http://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-to-announce-third-quarter-financial-results-and-provide-a-corporate-update-301144524.html

SOURCE Brainstorm Cell Therapeutics Inc

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BrainStorm Cell Therapeutics to Announce Third Quarter Financial Results and Provide a Corporate Upd - PharmiWeb.com

By Claudia Paba Prada, MD

For more than 30 years, oncologists have used immunotherapy to treat cancer, harnessing the strength of the patients own immune system to fight the disease. For many, it has been a welcome alternative or supplement to more traditional chemotherapy, radiation, and surgical options.

The disease I specialize in, multiple myeloma, has no cure, but patients can maintain quality of life with treatment combinations. These individuals have cancer cells form in plasma cells within bone marrow, crowding out healthy (red and white) blood cells and damaging bones, the immune system, and kidneys. We use immunotherapy in combination with chemotherapy to treat cancerous plasma cells, transitioning to different drugs when the cancer mutates and becomes resistant to the previously prescribed treatment. Our goal is to get patients to a stem cell transplant or, if they arent an appropriate candidate, to utilize a combination of drugs to kill myeloma cells. We then continue maintenance therapy to keep cancer cells dormant and preserve their existing lifestyle.

Its critical that we never stop studying the biology of the diseases we see, since each patient is different and there is no one-size-fits-all treatment. What approaches have been used previously, their toxicity, and the patients comorbidities (diabetes, heart issues, etc.) all factor into what may or may not be the appropriate next step. With younger, newly diagnosed patients, a more aggressive approach to get to transplantation may be pursued. In older patients, the goal is usually to get to some level of remission, even if that isnt a permanent solution.

Some myeloma patients, however, dont respond to any of the available chemotherapy drugs or may have a cancer relapse after their transplant. Thats why there is excitement within the cancer community about clinical trials were participating in at the

Moffitt Malignant Hematology and Cellular Therapy Program at Memorial Hospital West that have increased what were able to accomplish through immunotherapy.

The new approach is called CAR-T cell therapy and its administered like a blood transfusion after the patients own T cells are reprogrammed to attack the cancer cells. This is done by genetically altering T cells so they produce synthetic molecules called chimeric antigen receptors, or CARs, which enable T cells to recognize and attach to a certain protein in tumor cells and kill them.

We see 70-80 new multiple myeloma cases each year and more than 300 with relapse disease so, while not every patient will be a CAR-T candidate, were hoping many more will be as the trial progresses. Were using drugs under research that are unavailable anywhere else in Florida for myeloma and expect to expand to include leukemia and lymphoma patients in the coming year.

All this work is being done as we establish a myeloma-specific institute at Moffitt/Memorial that will be the only one of its type in Broward and Palm Beach counties. Bringing specialists together and providing South Floridians access to clinical trials is part of what were planning, but its also important to address the whole person and not just the disease. Thats why were already collaborating with the Leukemia and Lymphoma Society of Broward County and have established a support group for myeloma patients and their caregivers. The group will address issues related to a cancer diagnosis and provide opportunities for attendees to discuss concerns, anxieties, feelings related to their illness, treatment, and connected issues. Meetings, even the virtual ones were having during COVID-19, are designed to offer mutual support and information to members by connecting them to others whose situations are similar to their own.

My own journey has taken me from my home country of Colombia to an internal medicine residency in Philadelphia, hematology/oncology fellowship in Memphis, and an advanced fellowship in hematologic malignancies at Dana Farber Cancer Institute in Boston. I was at Dana Farber for seven years before relocating to South Florida in 2017. I joined the Moffitt team at Memorial Hospital West in July and am anxious to further the research and treatment of multiple myeloma at one of the nations leading cancer centers. CAR-T cellular therapy is one of the ways we can get there together.

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New Weapons in the Battle Against Blood Cancers: Current Articles - South Florida Hospital News

Researchers at Cima and the Clinica Universidad de Navarra (Spain) have led an international study identifying the cardiac cells responsible for repairing the damage to this organ after infarction. These "restorative" cells are a subpopulation of cardiac fibroblasts that play a fundamental role in the creation of the collagen scar needed to avoid the rupture of the ventricular wall. The research also reveals the molecular mechanisms involved in the activation of these cells and the regulation of their function.

This finding, in which basic and clinical researchers have participated, will permit the identification of new therapeutic targets and the development of targeted therapies which will control the healing process of the heart after infarction.

The study has been published in the latest issue of the journal Circulation, the leading scientific journal of the American Heart Association.Characterization of the reparative cardiac fibroblasts

Cardiac fibroblasts are one of the fundamental components of the heart. These cells play an essential role in maintaining the structure and mechanism of this vital organ. "Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Therefore the object of our study was to determine their heterogeneity during the remodeling of the injured ventricle and to understand the mechanisms that regulate the function of these cells", said Dr Felipe Prsper, a researcher at Cima and the Clinica Universidad de Navarra, the leader of the study.

"Using single-cell transcription analysis techniques (single-cell RNA-seq), we identified a subpopulation within the cardiac fibroblasts, which we have named Reparative Cardiac Fibroblasts (RCF) due to their role after the cardiac injury. We have found that, when a patient has a heart attack, these RCF are activated and offer a fibrotic response due to which a collagen scar is generated to avoid the rupture of the cardiac tissue", stated Dr Prsper, who is also a member of the Red de Terapia Celular (TerCel) and the Instituto de Investigacin Sanitaria de Navarra (IdiSNA).

CTHRC1, a protein related to collagen and essential for the regenerative process

In the detailed molecular study, the researchers have found that the RCF have a unique transcriptional profile, that is to say, a specific information pattern for the expression of the genes involved in their cardiac function. "Among the main differential markers of the transcriptome of these cells, we have identified the CTHRC1 protein (Collagen Triple Helix Repeat Containing 1), a molecule with a fundamental role in the fibrotic response after myocardial infarction. Specifically, this protein participates in the collagen synthesis of the extracellular cardiac matrix and is crucial for the process of ventricular remodeling", in the words of Adrin Ruiz-Villalba, a researcher on the Regenerative Medicine Program at Cima and first author of the article.

These results "suggest that the RCF activates the healing scar process of the cardiac lesion by secreting the CTHRC1 protein. Thus, this molecule may be considered as a biomarker associated with the physiological condition of the injured heart and a potential therapeutic target for patients who have suffered a heart attack or have dilated cardiomyopathy", stated Ruiz-Villalba, who is also a researcher at IdiSNA. In addition to Cima and the Clinica Universidad de Navarra, basic and clinical researchers from the United States, Belgium and Austria have taken part in this research.

This work falls within the framework of the Cell Therapy and Regenerative Medicine research line being carried out at Cima and the Clinica Universidad de Navarra, aimed at understanding the regenerative potential of stem cells and their therapeutic application in different diseases such as cardiovascular ones. Specifically, this study is linked to the BRAV? project, an international research project combining bioengineering and cardiac stem cells to restore the function of an infarcted heart. BRAV? is an H2020 funded program by the European Union (H2020-SC1-BHC-07-2019-874827).

Reference: Ruiz-Villalba A, Romero JP, Hernandez SC, et al.Single-Cell RNA-seq Analysis Reveals a Crucial Role for Collagen Triple Helix Repeat Containing 1 (CTHRC1) Cardiac Fibroblasts after Myocardial Infarction. Circ, 2020. doi:10.1161/CIRCULATIONAHA.119.044557

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Researchers Discover Cells That Heal Cardiac Damage After Infarction - Technology Networks

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press release: The UW has a long history of pioneering medical advancements that have transformed the world. From performing the first bone marrow transplant in the United States to cultivating the first laboratory-derived human embryonic stem cells. Now, where will UW medical research go next?

On the next Wisconsin Medicine Livestream, meet trailblazing doctors, researchers, and medical leaders who are charting a bold course to completely alter the health care landscape. During this insightful panel discussion, well explore how gene therapy and cell replacements could hold the keys to treating inherited and acquired blindness. Youll also discover the remarkable potential in xenotransplantation where nonhuman animal source organs are transplanted into human recipients. In addition, you will learn about UW Healths journey to build a multidisciplinary program to serve the community. These, and other, fascinating developments in treatment and care are happening right now at the UW and are the future of medicine. The presentation will be moderated by Robert Golden, the dean of the University of WisconsinMadisons School of Medicine and Public Health.

Our Guests:

David Gamm, professor, Department of Ophthalmology and Visual Sciences; Emmett A. Humble Distinguished Director, McPherson Eye Research Institute; Sandra Lemke Trout Chair in Eye Research

Dr. Gamms lab is at the forefront in developing cell-based therapies to combat retinal degenerative diseases (RDDs). As the director of the McPherson Eye Research Institute and a member of the Waisman Center Stem Cell Research Program, the UW Stem Cell and Regenerative Medicine Center, and the American Society for Clinical Investigation, his efforts are directed toward basic and translational retinal stem cell research. The Gamm Lab uses induced pluripotent stem cells to create retinal tissues composed of authentic human photoreceptor cells rods and cones that can detect light and initiate visual signals in a dish. The aims of his laboratory are to investigate the cellular and molecular events that occur during human retinal development and to generate cells for use in retinal disease modeling and cell replacement therapies. In collaboration with other researchers at UWMadison and around the world, the lab is developing methods to produce and transplant photoreceptors and/or retinal pigment epithelium (RPE) in preparation for future clinical trials. At the same time, the Gamm Lab uses lab-grown photoreceptor and RPE cells to test and advance a host of other experimental treatments, including gene therapies. In so doing, the lab seeks to delay or reverse the effects of blinding disorders, such as retinitis pigmentosa and age-related macular degeneration, and to develop or codevelop effective interventions for these RDDs at all stages of disease.

Dhanansayan Shanmuganayagam, assistant professor, Department of Surgery, School of Medicine and Public Health; Department of Animal and Dairy Sciences, UWMadison; director, Biomedical, and Genomic Research Group

Dr. Shanmuganayagams research focuses on the development and utilization of pigs as homologous models to close the translational gap in human disease research, taking advantage of the overwhelming similarities between pigs and humans in terms of genetics, anatomy, physiology, and immunology. He and his colleagues created the human-sized Wisconsin Miniature Swine breed that is unique to the university. The breed exhibits greater physiological similarity to humans, particularly in vascular biology and in modeling metabolic disorders and obesity. He currently leads genetic engineering of swine at the UW. His team has created more than 15 genetic porcine models including several of pediatric genetic cancer-predisposition disorders such as neurofibromatosis type 1 (NF1). In the context of NF1, his lab is studying the role of alternative splicing of the nf1 gene on the tissue-specific function of neurofibromin and whether gene therapy to modulate the regulation of this splicing can be used as a viable treatment strategy for children with the disorder.

Dr. Shanmuganayagam is also currently leading the efforts to establish the University of Wisconsin Center for Biomedical Swine Research and Innovation (CBSRI) that will leverage the translatability of research in pig models and UWMadisons unique swine and biomedical research infrastructure, resources, and expertise to conduct innovative basic and translational research on human diseases. The central mission of CBSRI is to innovate and accelerate the discovery and development of clinically relevant therapies and technologies. The center will also serve to innovate graduate and medical training. As the only center of its kind in the United States, CBSRI will make UWMadison a hub of translational research and industry-partnered biomedical innovation.

Petros Anagnostopoulos, surgeon in chief, American Family Childrens Hospital; chief, Section of Pediatric Cardiothoracic Surgery; professor, Department of Surgery, Division of Cardiothoracic Surgery

Dr. Anagnostopoulos is certified by the American Board of Thoracic Surgery and the American Board of Surgery. He completed two fellowships, one in cardiothoracic surgery at the University of Pittsburgh School of Medicine and a second in pediatric cardiac surgery at the University of California, San Francisco School of Medicine. He completed his general surgery residency at Henry Ford Hospital in Detroit. Dr. Anagnostopoulos received his MD from the University of Athens Medical School, Greece. His clinical interests include pediatric congenital heart surgery and minimally invasive heart surgery.

Dr. Anagnostopoulos specializes in complex neonatal and infant cardiac reconstructive surgery, pediatric heart surgery, adult congenital cardiac surgery, single ventricle palliation, extracorporeal life support, extracorporeal membrane oxygenation, ventricular assist devices, minimally invasive cardiac surgery, hybrid surgical-catheterization cardiac surgery, off-pump cardiac surgery, complex mitral and tricuspid valve repair, aortic root surgery, tetralogy of Fallot, coronary artery anomalies, Ross operations, obstructive cardiomyopathy, and heart transplantation.

When: Tuesday, Sept. 29, at 7 p.m. CDT

Where: Wisconsin Medicine Livestream: wiscmedicine.org/programs/ending-alzheimers

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ONLINE: The Future of Medicine - Isthmus

News Release

Monday, September 28, 2020

Findings show deficits in the electrical activity of cortical cells; possible targets for treatment for 22q11.2 deletion syndrome.

A genetic study has identified neuronal abnormalities in the electrical activity of cortical cells derived from people with a rare genetic disorder called 22q11.2 deletion syndrome. The overexpression of a specific gene and exposure to several antipsychotic drugs helped restore normal cellular functioning. The study, funded by the National Institutes of Health (NIH) and published in Nature Medicine, sheds light on factors that may contribute to the development of mental illnesses in 22q11.2 deletion syndrome and may help identify possible targets for treatment development.

22q11.2 deletion syndrome is a genetic disorder caused by the deletion of a piece of genetic material at location q11.2 on chromosome 22. People with 22q11.2 deletion syndrome can experience heart abnormalities, poor immune functioning, abnormal palate development, skeletal differences, and developmental delays. In addition, this deletion confers a 20-30% risk for autism spectrum disorder (ASD) and an up to 30-fold increase in risk for psychosis. 22q11.2 deletion syndrome is the most common genetic copy number variant found in those with ASD, and up to a quarter of people with this genetic syndrome develop a schizophrenia spectrum disorder.

This is the largest study of its type in terms of the number of patients who donated cells, and it is significant for its focus on a key genetic risk factor for mental illnesses, said David Panchision, Ph.D., chief of the Developmental Neurobiology Program at the NIHs National Institute of Mental Health. Importantly, this study shows consistent, specific patient-control differences in neuronal function and a potential mechanistic target for developing new therapies for treating this disorder.

While some effects of this genetic syndrome, such as cardiovascular and immune concerns, can be successfully managed, the associated psychiatric effects have been more challenging to address. This is partly because the underlying cellular deficits in the central nervous system that contribute to mental illnesses in this syndrome are not well understood. While recent studies of 22q11.2 deletion syndrome in rodent models have provided some important insights into possible brain circuit-level abnormalities associated with the syndrome, more needs to be understood about the neuronal pathways in humans.

To investigate the neural pathways associated with mental illnesses in those with 22q11.2 deletion syndrome, Sergiu Pasca, M.D., associate professor of psychiatry and behavioral sciences at Stanford University, Stanford, California, along with a team of researchers from several other universities and institutes, created induced pluripotent stems cells cells derived from adult skin cells reprogramed into an immature stem-cell-like state from 15 people with 22q11.2 deletion and 15 people without the syndrome. The researchers used these cells to create, in a dish, three-dimensional brain organoids that recapitulate key features of the developing human cerebral cortex.

What is exciting is that these 3D cellular models of the brain self-organize and, if guided to resemble the cerebral cortex, for instance, contain functional glutamatergic neurons of deep and superficial layers and non-reactive astrocytes and can be maintained for years in culture. So, there is a lot of excitement about the potential of these patient-derived models to study neuropsychiatric disease, said Dr. Pasca.

The researchers analyzed gene expression in the organoids across 100 days of development. They found changes in the expression of genes linked to neuronal excitability in the organoids that were created using cells from individuals with 22q11.2 deletion syndrome. These changes prompted the researchers to take a closer look at the properties associated with electrical signaling and communication in these neurons. One way neurons communicate is electrically, through controlled changes in the positive or negative charge of the cell membrane. This electrical charge is created when ions, such as calcium, move into or out of the cell through small channels in the cells membrane. The researchers imaged thousands of cells and recorded the electrical activity of hundreds of neurons derived from individuals with 22q11.2 deletion syndrome and found abnormalities in the way calcium was moved into and out of the cells that were related to a defect in the resting electrical potential of the cell membrane.

A gene called DGCR8 is part of the genetic material deleted in 22q11.2 deletion syndrome, and it has been previously associated with neuronal abnormalities in rodent models of this syndrome. The researchers found that heterozygous loss of this gene was sufficient to induce the changes in excitability they had observed in 22q11.2-derived neurons and that overexpression of DGCR8 led to partial restoration of normal cellular functioning. In addition, treating 22q11.2 deletion syndrome neurons with one of three antipsychotic drugs (raclopride, sulpiride, or olanzapine) restored the observed deficits in resting membrane potential of the neurons within minutes.

We were surprised to see that loss in control neurons and restoration in patient neurons of the DGCR8 gene can induce and, respectively, restore the excitability, membrane potential, and calcium defects, said Pasca. Moving forward, this gene or the downstream microRNA(s) or the ion channel/transporter they regulate may represent novel therapeutic avenues in 22q11.2 deletion syndrome.

Grants:MH107800; MH100900; MH085953; MH060233; MH094714

About the National Institute of Mental Health (NIMH):The mission of theNIMHis to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit theNIMH website.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

Khan, T. A., Revah, O., Gordon, A., Yoon, S., Krawisz, A. K., Goold, C., Sun, Y., Kim, C., Tian, Y., Li, M., Schaepe, J. M., Ikeda, K., Amin, N. D., Sakai, N., Yazawa, M., Kushan, L., Nishino, S., Porteus, M. H., Rapoport, J. L. Paca, S. (2020). Neuronal defects in a human cellular model of 22q11.2 deletion syndrome. Nature Medicine. doi: 10.1038/s41591-020-1043-9

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The rest is here:
funded study sheds light on abnormal neural function in rare genetic disorder - National Institutes of Health

This press release was orginally distributed by SBWire

Albany, NY -- (SBWIRE) -- 09/23/2020 -- Transparency Market Research (TMR) has published a new report on the global cell separation technology market for the forecast period of 20192027. According to the report, the global cell separation technology market was valued at ~ US$ 5 Bn in 2018, and is projected to expand at a double-digit CAGR during the forecast period.

Overview

Cell separation, also known as cell sorting or cell isolation, is the process of removing cells from biological samples such as tissue or whole blood. Cell separation is a powerful technology that assists biological research. Rising incidences of chronic illnesses across the globe are likely to boost the development of regenerative medicines or tissue engineering, which further boosts the adoption of cell separation technologies by researchers.

Expansion of the global cell separation technology market is attributed to an increase in technological advancements and surge in investments in research & development, such as stem cell research and cancer research. The rising geriatric population is another factor boosting the need for cell separation technologies Moreover, the geriatric population, globally, is more prone to long-term neurological and other chronic illnesses, which, in turn, is driving research to develop treatment for chronic illnesses. Furthermore, increase in the awareness about innovative technologies, such as microfluidics, fluorescent-activated cells sorting, and magnetic activated cells sorting is expected to propel the global cell separation technology market.

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North America dominated the global cell separation technology market in 2018, and the trend is anticipated to continue during the forecast period. This is attributed to technological advancements in offering cell separation solutions, presence of key players, and increased initiatives by governments for advancing the cell separation process. However, insufficient funding for the development of cell separation technologies is likely to hamper the global cell separation technology market during the forecast period. Asia Pacific is expected to be a highly lucrative market for cell separation technology during the forecast period, owing to improving healthcare infrastructure along with rising investments in research & development in the region.

Rising Incidences of Chronic Diseases, Worldwide, Boosting the Demand for Cell Therapy

Incidences of chronic diseases such as diabetes, obesity, arthritis, cardiac diseases, and cancer are increasing due to sedentary lifestyles, aging population, and increased alcohol consumption and cigarette smoking. According to the World Health Organization (WHO), by 2020, the mortality rate from chronic diseases is expected to reach 73%, and in developing counties, 70% deaths are estimated to be caused by chronic diseases. Southeast Asia, Eastern Mediterranean, and Africa are expected to be greatly affected by chronic diseases. Thus, the increasing burden of chronic diseases around the world is fuelling the demand for cellular therapies to treat chronic diseases. This, in turn, is driving focus and investments on research to develop effective treatments. Thus, increase in cellular research activities is boosting the global cell separation technology market.

Increase in Geriatric Population Boosting the Demand for Surgeries

The geriatric population is likely to suffer from chronic diseases such as cancer and neurological disorders more than the younger population. Moreover, the geriatric population is increasing at a rapid pace as compared to that of the younger population. Increase in the geriatric population aged above 65 years is projected to drive the incidences of Alzheimer's, dementia, cancer, and immune diseases, which, in turn, is anticipated to boost the need for corrective treatment of these disorders. This is estimated to further drive the demand for clinical trials and research that require cell separation products. These factors are likely to boost the global cell separation technology market.

According to the United Nations, the geriatric population aged above 60 is expected to double by 2050 and triple by 2100, an increase from 962 million in 2017 to 2.1 billion in 2050 and 3.1 billion by 2100.

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Productive Partnerships in Microfluidics Likely to Boost the Cell Separation Technology Market

Technological advancements are prompting companies to innovate in microfluidics cell separation technology. Strategic partnerships and collaborations is an ongoing trend, which is boosting the innovation and development of microfluidics-based products. Governments and stakeholders look upon the potential in single cell separation technology and its analysis, which drives them to invest in the development of microfluidics. Companies are striving to build a platform by utilizing their expertise and experience to further offer enhanced solutions to end users.

Stem Cell Research to Account for a Prominent Share

Stem cell is a prominent cell therapy utilized in the development of regenerative medicine, which is employed in the replacement of tissues or organs, rather than treating them. Thus, stem cell accounted for a prominent share of the global market. The geriatric population is likely to increase at a rapid pace as compared to the adult population, by 2030, which is likely to attract the use of stem cell therapy for treatment. Stem cells require considerably higher number of clinical trials, which is likely to drive the demand for cell separation technology, globally. Rising stem cell research is likely to attract government and private funding, which, in turn, is estimated to offer significant opportunity for stem cell therapies.

Biotechnology & Pharmaceuticals Companies to Dominate the Market

The number of biotechnology companies operating across the globe is rising, especially in developing countries. Pharmaceutical companies are likely to use cells separation techniques to develop drugs and continue contributing through innovation. Growing research in stem cell has prompted companies to own large separate units to boost the same. Thus, advancements in developing drugs and treatments, such as CAR-T through cell separation technologies, are likely to drive the segment.

As per research, 449 public biotech companies operate in the U.S., which is expected to boost the biotechnology & pharmaceutical companies segment. In developing countries such as China, China Food and Drug Administration (CFDA) reforms pave the way for innovation to further boost biotechnology & pharmaceutical companies in the country.

Global Cell Separation Technology Market: Prominent Regions

North America to Dominate Global Market, While Asia Pacific to Offer Significant Opportunity

In terms of region, the global cell separation technology market has been segmented into five major regions: North America, Europe, Asia Pacific, Latin America, and the Middle East & Africa. North America dominated the global market in 2018, followed by Europe. North America accounted for a major share of the global cell separation technology market in 2018, owing to the development of cell separation advanced technologies, well-defined regulatory framework, and initiatives by governments in the region to further encourage the research industry. The U.S. is a major investor in stem cell research, which accelerates the development of regenerative medicines for the treatment of various long-term illnesses.

The cell separation technology market in Asia Pacific is projected to expand at a high CAGR from 2019 to 2027. This can be attributed to an increase in healthcare expenditure and large patient population, especially in countries such as India and China. Rising medical tourism in the region and technological advancements are likely to drive the cell separation technology market in the region.

Launching Innovative Products, and Acquisitions & Collaborations by Key Players Driving Global Cell Separation Technology Market

The global cell separation technology market is highly competitive in terms of number of players. Key players operating in the global cell separation technology market include Akadeum Life Sciences, STEMCELL Technologies, Inc., BD, Bio-Rad Laboratories, Inc., Miltenyi Biotech, 10X Genomics, Thermo Fisher Scientific, Inc., Zeiss, GE Healthcare Life Sciences, PerkinElmer, Inc., and QIAGEN.

These players have adopted various strategies such as expanding their product portfolios by launching new cell separation kits and devices, and participation in acquisitions, establishing strong distribution networks. Companies are expanding their geographic presence in order sustain in the global cell separation technology market. For instance, in May 2019, Akadeum Life Sciences launched seven new microbubble-based products at a conference. In July 2017, BD received the U.S. FDA's clearance for its BD FACS Lyric flow cytometer system, which is used in the diagnosis of immunological disorders.

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Cell Separation Technology Market: Productive Partnerships in Microfluidics Likely to Boost the Market Growth - Press Release - Digital Journal

Sept. 20, 2020 14:20 UTC

KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the presentation of new data for three investigational medicines in Mercks diverse and expansive oncology pipeline: vibostolimab (MK-7684), an anti-TIGIT therapy; MK-4830, a first-in-class anti-ILT4 therapy; and MK-6482, an oral HIF-2 inhibitor. Data from cohort expansions of a Phase 1b trial evaluating vibostolimab, as monotherapy and in combination with KEYTRUDA, Mercks anti-PD-1 therapy, in patients with metastatic non-small cell lung cancer (NSCLC; Abstract #1410P and Abstract #1400P), and first-time Phase 1 data for MK-4830 in patients with advanced solid tumors (Abstract #524O), demonstrated acceptable safety profiles for these two investigational medicines and early signals of anti-tumor activity. Additionally, late-breaking Phase 2 data for MK-6482 showed anti-tumor responses in von Hippel-Lindau (VHL) disease patients with clear cell renal cell carcinoma (RCC) and other tumors (Abstract #LBA26).

The new data for these three investigational medicines are encouraging and highlight continued momentum in our rapidly expanding oncology pipeline, Dr. Eric H. Rubin, senior vice president, early-stage development, clinical oncology, Merck Research Laboratories. Over the past five years, KEYTRUDA has become foundational in the treatment of certain advanced cancers. Our broad oncology portfolio and promising pipeline candidates are a testament to our commitment to bring forward innovative new medicines to address unmet medical needs in cancer care.

Vibostolimab (Anti-TIGIT Therapy): Early Findings in Metastatic NSCLC (Abstract #1410P and Abstract #1400P)

Vibostolimab in combination with KEYTRUDA was evaluated in patients with metastatic NSCLC who had not previously received antiPD-1/PD-L1 therapy, but the majority of whom had received >1 prior lines of therapy (73%, n=30/41) in Abstract #1410P. In Part B of the first-in-human, open-label, Phase 1 trial (NCT02964013) all patients received vibostolimab (200 or 210 mg) in combination with KEYTRUDA (200 mg) on Day 1 of each three-week cycle for up to 35 cycles. The primary endpoints of the study were safety and tolerability. Secondary endpoints included objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS) based on investigator review per RECIST v1.1. In this anti-PD-1/PD-L1 nave study, vibostolimab in combination with KEYTRUDA had a manageable safety profile and demonstrated promising anti-tumor activity. Treatment-related adverse events (TRAEs) with vibostolimab in combination with KEYTRUDA occurred in 34 patients (83%). The most frequent TRAEs (20%) were pruritus (34%), hypoalbuminemia (29%) and pyrexia (20%). Grade 3-5 TRAEs occurred in six patients (15%). No deaths due to TRAEs occurred. Across all patients enrolled, treatment with vibostolimab in combination with KEYTRUDA demonstrated an ORR of 29% (95% CI, 16-46) and median PFS was 5.4 months (95% CI, 2.1-8.2). The median DOR was not reached (range, 4 to 17+ months). Among patients whose tumors express PD-L1 (tumor proportion score [TPS] 1%) (n=13), the ORR was 46% (95% CI, 19-75) and median PFS was 8.4 months (95% CI, 3.9-10.2). Among patients whose tumors express PD-L1 (TPS <1%) (n=12), the ORR was 25% (95% CI, 6-57), and median PFS was 4.1 months (95% CI, 1.9-not reached [NR]). PD-L1 status was not available for 16 patients. Median follow-up for the study was 11 months (range, 7 to 18).

Additional data from a separate cohort of the same Phase 1b trial evaluated vibostolimab as monotherapy (n=41) and in combination with KEYTRUDA (n=38) in patients with metastatic NSCLC whose disease progressed on prior anti-PD-1/PD-L1 therapy (Abstract #1400P). In the study, 78% of patients had received >2 lines of prior therapy. In the study, patients received vibostolimab monotherapy (200 or 210 mg) or vibostolimab (200 or 210 mg) in combination with KEYTRUDA (200 mg) on Day 1 of each three-week cycle for up to 35 cycles. The primary endpoints of the study were safety and tolerability. Secondary endpoints included ORR and DOR. Vibostolimab as monotherapy or in combination with KEYTRUDA had a manageable safety profile and demonstrated modest anti-tumor activity in patients whose disease was refractory to PD-1/PD-L1 inhibition, most of whom had previously received several lines of therapy for advanced disease prior to enrollment. Grade 3-5 TRAEs occurred in 15% of patients receiving vibostolimab monotherapy and 13% of patients receiving vibostolimab in combination with KEYTRUDA. The most common TRAEs (10% in either arm) were pruritus, fatigue, rash, arthralgia and decreased appetite. One patient died due to treatment-related pneumonitis in the vibostolimab and KEYTRUDA combination arm. The ORR was 7% (95% CI, 2-20) with vibostolimab monotherapy and 5% (95% CI, <1-18) with vibostolimab in combination with KEYTRUDA. The median DOR was 9 months (range, 9 to 9) with vibostolimab monotherapy and 13 months (range, 4+ to 13) with vibostolimab in combination with KEYTRUDA.

Data from these cohort expansion studies are encouraging and support the continued development of vibostolimab, which is being evaluated alone and in combination with KEYTRUDA across multiple solid tumors, including NSCLC and melanoma. In the ongoing Phase 2 KEYNOTE-U01 umbrella study (NCT04165798), substudy KEYNOTE-01A (NCT04165070) is evaluating vibostolimab in combination with KEYTRUDA plus chemotherapy for the first-line treatment of patients with advanced NSCLC who had not received prior treatment with an anti-PD-1/PD-L1. Merck plans to initiate a Phase 3 study of vibostolimab in NSCLC in the first half of 2021. Ongoing trials in melanoma include the Phase 1/2 KEYNOTE-U02 umbrella study comprised of three substudies evaluating vibostolimab in combination with KEYTRUDA across treatment settings (substudy 02A: NCT04305041, substudy 02B: NCT04305054 and substudy 02C: NCT04303169).

MK-4830 (Anti-ILT4 Therapy): Initial Results in Advanced Solid Tumors (Abstract #524O)

In this first-in-human Phase 1, open-label, multi-arm, multi-center, dose escalation study (NCT03564691), MK-4830, Mercks first-in-class anti-ILT4 therapy, was evaluated as monotherapy (n=50) and in combination with KEYTRUDA (n=34) in patients with advanced solid tumors. The majority of patients enrolled in the study (51%) had received three or more prior lines of therapy. MK-4830 was administered intravenously at escalating doses every three weeks alone or in combination with KEYTRUDA (200 mg every three weeks). The primary endpoints of the dose escalation part of the study were safety and tolerability; Pharmacokinetics was a secondary endpoint, and exploratory objectives included ORR per RECIST v1.1, evaluation of receptor occupancy and immune correlates of response in blood and tumor.

Findings showed that MK-4830 as monotherapy and in combination with KEYTRUDA had an acceptable safety profile and demonstrated dose-related evidence of target engagement in patients with advanced solid tumors. No dose-limiting toxicities were observed; the maximum-tolerated dose was not reached. Any-grade adverse events were consistent with those associated with KEYTRUDA. Treatment-related AEs occurred in 54% (n=28/52) of patients who received MK-4830 in combination with KEYTRUDA and 48% (n=24/50) of patients who received MK-4830 monotherapy; the majority were Grade 1 and 2. Preliminary efficacy data showed an ORR of 24% (n=8/34) in patients who received MK-4830 in combination with KEYTRUDA. All responses occurred in heavily pretreated patients, including five who had progressed on prior anti-PD-1 therapy (n=5/11). Some patients received more than one year of treatment, and treatment is ongoing in several patients.

These early data support the continued development of MK-4830 in combination with KEYTRUDA in patients with advanced solid tumors. Expansion cohorts of this study include pancreatic adenocarcinoma, glioblastoma, head and neck squamous cell carcinoma (recurrent or metastatic; PD-L1 positive), advanced NSCLC and gastric cancer.

MK-6482 (HIF-2 Inhibitor): Results in VHL-Associated RCC and Non-RCC Tumors (Abstract #LBA26)

In this Phase 2, open-label, single-arm trial, MK-6482 was evaluated for the treatment of VHL-associated RCC (NCT03401788). New data include findings for MK-6482 in VHL patients with non-RCC tumors and updated data in VHL patients with RCC. First-time data in VHL-associated RCC were presented in the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting. The study enrolled adult patients with a pathogenic germline VHL variation, measurable localized or non-metastatic RCC, no prior systemic anti-cancer therapy, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients received MK-6482 120 mg orally once daily until disease progression, unacceptable toxicity, or investigators or patients decision to withdraw. The primary endpoint was ORR of VHL-associated RCC tumors per RECIST v1.1 by independent radiology review. Secondary endpoints included DOR, time to response, PFS, efficacy in non-RCC tumors, and safety and tolerability.

Promising clinical activity continues to be observed with MK-6482 in treatment-nave patients with VHL-associated RCC. Among 61 patients, results showed a confirmed ORR of 36.1% (95% CI, 24.2-49.4); all responses were partial responses, and 38% of patients had stable disease. The median time to response was 31.1 weeks (range, 11.9 to 62.3), and median DOR was not yet reached (range, 11.9 to 62.3 weeks). Additionally, 91.8% (n=56) of patients had a decrease in size of target lesions. Median PFS has not been reached, and the PFS rate at 52 weeks was 98.3%. Median duration of treatment was 68.7 weeks (range, 18.3 to 104.7), and 91.8% of patients were still on therapy after a minimum follow-up of 60 weeks.

In patients with non-RCC tumors, results in those with pancreatic lesions (n=61) showed a confirmed ORR of 63.9% (95% CI, 50.6-75.8), with four complete responses and 35 partial responses. Additionally, 34.4% had stable disease. In those with central nervous system (CNS) hemangioblastoma (n=43), results showed a confirmed ORR of 30.2% (95% CI, 17.2-46.1), with five complete responses and eight partial responses. Additionally, 65.1% had stable disease. In patients with retinal lesions (n=16), 93.8% of patients had improved or stable response.

In this Phase 2 study, TRAEs occurred in 98.4% of patients, and there were no Grade 4-5 TRAEs. The most common all-cause adverse events (20%) were anemia (90.2%), fatigue (60.7%), headache (37.7%), dizziness (36.1%) and nausea (31.1%). Grade 3 all-cause adverse events included anemia (6.6%), fatigue (4.9%) and dyspnea (1.6%). One patient discontinued treatment due to a TRAE (Grade 1 dizziness).

As announced, data spanning more than 15 types of cancer will be presented from Mercks broad oncology portfolio and investigational pipeline at the congress. A compendium of presentations and posters of Merck-led studies is available here. Follow Merck on Twitter via @Merck and keep up to date with ESMO news and updates by using the hashtag #ESMO20.

About Vibostolimab

Vibostolimab is an anti-TIGIT therapy discovered and developed by Merck. Vibostolimab binds to TIGIT and blocks the interaction between TIGIT and its ligands (CD112 and CD155), thereby activating T lymphocytes which help to destroy tumor cells. The effect of combining KEYTRUDA with vibostolimab blocking both the TIGIT and PD-1 pathways simultaneously is currently being evaluated across multiple solid tumors, including NSCLC and melanoma.

About MK-4830

MK-4830 is a novel antibody directed against the inhibitory immune checkpoint receptor immunoglobulin-like transcript 4 (ILT4). Unlike current T cell-targeted antibodies (e.g., anti-PD1, anti-CTLA-4), anti-ILT4 is believed to attenuate immunosuppression imposed by tolerogenic myeloid cells in the tumor microenvironment. MK-4830 is currently being evaluated alone and in combination with KEYTRUDA across multiple solid tumors as part of ongoing Phase 1 and 2 trials.

About MK-6482

MK-6482 is an investigational, novel, potent, selective, oral HIF-2 inhibitor that is currently being evaluated in a Phase 3 trial in advanced RCC (NCT04195750), a Phase 2 trial in VHL-associated RCC (NCT03401788), and a Phase 1/2 dose-escalation and dose-expansion trial in advanced solid tumors, including advanced RCC (NCT02974738). Proteins known as hypoxia-inducible factors, including HIF-2, can accumulate in patients when VHL, a tumor-suppressor protein, is inactivated. The accumulation of HIF-2 can lead to the formation of both benign and malignant tumors. This inactivation of VHL has been observed in more than 90% of RCC tumors. Research into VHL biology that led to the discovery of HIF-2 was awarded the Nobel Prize in Physiology or Medicine in 2019.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

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

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

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

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

Non-Small Cell Lung Cancer

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

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

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

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

Small Cell Lung Cancer

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

Head and Neck Squamous Cell Cancer

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

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

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

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

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

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

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

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

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

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

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

Gastric Cancer

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

Esophageal Cancer

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

Cervical Cancer

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

Hepatocellular Carcinoma

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

Merkel Cell Carcinoma

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

Renal Cell Carcinoma

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

Tumor Mutational Burden-High

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

Cutaneous Squamous Cell Carcinoma

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

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

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

Embryofetal Toxicity

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Immunotherapies that are currently being studied in multiple myeloma are discussed in this section under four headings: checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, bispecific antibodies, and antibody drug conjugates (fig 2).

Malignant plasma cells in most patients with multiple myeloma express the checkpoint programmed death-ligand 1, which is upregulated especially when exposed to inflammatory mediators such as interferon . Interaction of this checkpoint molecule with programmed cell death protein 1 on T cells limits their proliferation and cytotoxic activity.6869

The first study evaluating single agent nivolumab for relapsed multiple myeloma showed a response in only one of 27 patients.7071 Despite a lack of single agent activity, single arm trials combining checkpoint inhibitors with immunomodulatory imide drugs and dexamethasone because of the potential synergy72 look promising.7374

With these clinical data, three large randomized phase III trials were halted by the FDA in 2017 because of increased serious adverse events and deaths as well as decreased overall survival in the checkpoint inhibitor arm (pomalidomide and dexamethasone with and without pembrolizumab) in relapsed and refractory multiple myeloma (hazard ratio 1.61, 95% confidence interval 0.91 to 2.85),75 pomalidomide and dexamethasone with and without nivolumab in relapsed and refractory multiple myeloma (1.19, 0.64 to 2.20),76 and lenalidomide and dexamethasone with and without pembrolizumab in transplant ineligible patients with newly diagnosed multiple myeloma (2.06, 0.93 to 4.55)77).

These trials encourage caution with expedited timelines for future combination studies for drugs with limited single agent activity.7879 Future trials in multiple myeloma will need to be based on sound preclinical and clinical rationale with other partners and be conducted in heavily treated patients (with limited standard options) initially.

CAR T cells are human T cells that have been genetically modified and expanded in the laboratory before they are infused back into patients to target the tumor. The receptor on the surface of CAR T cells that targets the tumor antigens consists of several parts (fig 3): an extracellular, non-major histocompatibility complex restricted, targeting domain, usually derived from a single chain variable fragment of a monoclonal antibody; a spacer region; a transmembrane domain; an intracellular signaling domain including the CD3 activation domain; and a costimulatory domain (eg, CD28 or 4-1BB). The single chain variable fragment was originally derived from mice (hence the term chimeric), but many of the newer constructs are fully human.8081

Chimeric antigen receptor (CAR) T cell structure

CD3 positive T cells are obtained from patients (for autologous CAR T cells) or healthy donors (for allogeneic CAR T cells) via a process called leukapheresis. These T cells are expanded manifold in culture and activated using beads coated with anti-CD3 or anti-CD28 monoclonal antibodies or cell based artificial antigen presenting cells.82 The T cells are then transduced with a vector (usually either lentiviral or retroviral) that carries the gene encoding a receptor to an antigen present on the surface of tumor cells. This manufacturing process takes up to four weeks at a good manufacturing practices facility, and the CAR T cells can then be stored until needed by the patient. This delay means that the disease must not be rapidly progressing, so that the patient is able to wait until the CAR T product is ready; otherwise the patient will need bridging chemotherapy. Two to seven days before CAR T cell infusion, a patient receives lymphodepleting chemotherapy to make way for the CAR T cells that are subsequently given as an intravenous infusion. Once infused into patients, the CAR T cells encounter the antigen, proliferate, and kill the tumor cells (fig 4). These cells, therefore, combine the target specificity of a monoclonal antibody with the enhanced cytotoxicity of T cells without requiring human leucocyte antigen presentation of the target antigen.83

Chimeric antigen receptor (CAR) T cell treatment for multiple myelomasequence of events. CRS=cytokine release syndrome; ICANS=immune effector cell associated neurotoxicity syndrome

An ideal antigen is one that is widely and exclusively expressed on cancer cells but not on normal cells to enhance efficacy and reduce toxicity.8485 In multiple myeloma, most emerging immunotherapies (including CAR T cells) target B cell maturation antigen (BCMA), a type III transmembrane receptor, which is a promising target antigen.8687 BCMA is also known as tumor necrosis factor receptor superfamily member 17 or CD269. It is expressed in nearly all plasma cells (normal and malignant) although its expression is variable.88 BCMA promotes plasma cell survival and is induced during plasma cell differentiation89 by binding to ligands (a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF)) that are produced by osteoclasts.90 Increased levels of soluble BCMA are associated with high tumor burden in multiple myeloma and thus worse outcomes.91

CAR T cells targeting CD19 were approved by the FDA in 2017 for refractory large B cell lymphoma9293 and acute lymphoblastic leukemia,94 and are being used in clinical practice. The first study on CAR T cell treatment directed by BCMA opened in 2014 at the US National Cancer Institute.879596 Since then, about a dozen of different early phase clinical trials have been conducted on BCMA CAR T treatment for advanced multiple myeloma.9798 A detailed review outlining the differences in the construct, manufacturing, and clinical efficacy of these different products has been published previously.8186

This review focuses on four BCMA CAR T cell products that are currently being evaluated in registration (that is, for regulatory approval) phase I/II clinical trials for patients with relapsed and refractory multiple myeloma. These products include bb2121 (now known as idecabtagene vicleucel or ide-cel), JCARH125 (now known as orvacabtagene autoleucel or orva-cel), LCAR-B38M (now known as JNJ-4528), and P-Bcma-101. FDA approvals for some of these agents are anticipated in 2020-21 for relapsed and refractory multiple myeloma (fig 5; table 2). The high overall response rates of 60-100% seen in these trials in a highly refractory population is unprecedented, although the durability of these responses is still in question.

Four major constructs of chimeric antigen receptor (CAR) T cells targeting B cell maturation antigens (BCMA), currently in multicenter clinical trials investigating multiple myeloma. This figure does not include all BCMA constructs in multiple myeloma. ScFv=single chain variable fragment; VH only=variable-heavy chain only fragments

Summary of major multicenter clinical trials investigating multiple myeloma treatments*

The most advanced CAR T cell treatment targeting a BCMA is ide-cel (bb2121), which uses a lentiviral vector for CAR insertion and includes a 4-1BB costimulatory domain as well as a murine single chain variable fragment.114 In a phase I non-randomized, open label, multicenter trial in relapsed and refractory multiple myeloma (3 prior lines of treatment) for 33 patients treated at various doses,115 researchers found an overall response rate of 85% with a median progression free survival of 11.8 months. A higher overall response rate was seen at the higher dose levels and doses of 150-450106 CAR T cells were defined as the active dose.115 This dose is being tested currently in a multicenter, single arm, open label trial to evaluate bb2121 CAR T cells further in relapsed and refractory multiple myeloma; the trial has completed enrolment of 149 patients worldwide. Preliminary results show an overall response rate of 73% (complete response rate 33%) and median progression free survival of 8.8 months in 128 patients treated at doses of 150-450106 cells (table 2).99 Fifty four patients treated at the highest dose level of 450106 cells had an overall response rate of 82% and a median progression free survival of 12.1 months.99 These results have been submitted to regulatory agencies including the FDA and European Medicines Agency for treatment for advanced multiple myeloma.

Orva-cel (JCARH125) is another second generation CAR product with a fully human B cell derived single chain variable fragment, a 4-1BB costimulatory domain, and optimized manufacturing (predefined CD4:CD8 ratio) that is derived from preclinical work at Memorial Sloan Kettering Cancer Center. The preliminary data for the multicenter phase I/II EVOLVE study were presented at the American Society of Clinical Oncology meeting in 2020. These patients had received a median of six prior treatments. They received escalating doses of 50-600106 cells. The results for 62 patients treated at the 300-600106 cells dose range showed an overall response rate of 92% (complete response rate 36%).100101 The trial is currently enrolling at the recommended phase II dose of 600106 cells (table 2).

The LCAR-B38M CAR construct was developed initially in China and is currently being pursued in the US and globally as JNJ-4528 (table 2). It consists of two llama derived variable-heavy chain only fragments that target two epitopes of BCMA designed to confer avidity. In a phase I/II study in China, researchers found deep durable responses with a median progression free survival of 19.9 months and a manageable safety profile in relapsed and refractory multiple myeloma, although the patients in this study were treated earlier in their disease course with a median of three prior lines of treatment and were therefore less heavily pre-treated.102103104105 In the US and Europe, a multicenter phase Ib/II clinical trial of this CAR construct as JNJ-4528 in relapsed and refractory multiple myeloma (3 prior lines of treatment) was conducted to confirm the findings of the LEGEND-2 study. Preliminary results of the phase Ib portion showed an overall response rate of 100% (complete response rate 86%) in patients with a median of five prior lines of treatment (table 2).106107 The phase II portion is fully enrolled, and phase II and III studies have been initiated.

P-BCMA-101 is uniquely manufactured using the non-viral piggyBac gene editing system, which is less costly, produces cells with a high percentage of favorable stem cell memory phenotype T cells, and has the ability to include a safety switch. The binding molecule for this product is not a single chain variable fragment but a small fully human fibronectin domain (Centyrin) that has higher specificity and potentially less immunogenicity. In a phase I dose escalation trial, the overall response rate was 63% with a median progression free survival of 9.5 months in 19 evaluable patients108 (table 2).

CAR T cell treatments have a unique toxicity profile where patients can develop side effects such as cytokine release syndrome and neurotoxicity that has been recently termed immune effector cell associated neurotoxicity syndrome (ICANS).116 Cytokine release syndrome has been defined as a disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, or hypoxia caused by the release of cytokines from cells. The American Society for Transplantation and Cellular Therapy has developed a consensus grading system for cytokine release syndrome, which depends on the severity and presence of fever, hypotension, or hypoxia (table 3).116

American Society for Transplantation and Cellular Therapy consensus grading for cytokine release syndrome (CRS)116

ICANS has been defined as a disorder involving the central nervous system following any immunotherapy that results in the activation or engagement of endogenous or infused T cells or other immune effector cells. Symptoms or signs can be progressive and could include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral edema.116 It includes four grades that are determined by the ICE score (immune effector cell associated encephalopathy score, which provides objectivity to grading encephalopathy), level of consciousness, seizure, motor findings, and elevated intracranial pressure or cerebral edema (table 4).116 Management of ICANS and cytokine release syndrome is based on grading and involves supportive care, steroids, and interleukin blocking agents.117118 Interleukin 6 blocking agents (tocilizumab and siltuximab) with or without steroids are the mainstay of management for cytokine release syndrome, whereas steroids are the mainstay for the management of neurotoxicity. Another potential agent for managing these symptoms includes the interleukin 1 blocking agent anakinra.119

American Society for Transplantation and Cellular Therapy consensus grading for immune effector cell associated neurotoxicity syndrome (ICANS) in adults116

All the clinical trials on BCMA CAR T cell treatments had a high incidence of cytokine release syndrome (>80%) except for P-BCMA-101, which seemed to have a substantially lower incidence (10%). Despite this, severe cytokine release syndrome (that is, grade 3) is seen in less than 10% of patients. Neurotoxicity was reported in less than 20% of patients with severe neurotoxicity (grade 3) in less than 7% of patients. Another common side effect is cytopenia, which has also been thought to be secondary to the lymphodepleting chemotherapy, ongoing CAR T cell activity, and disruption of hematopoiesis showing severe hypocellularity in the bone marrow, but most patients recover with time.120121

Early recognition of cytokine release syndrome and ICANS and prompt intervention after CAR T cell treatment is vital to prevent serious consequences, although the optimal timing for intervention and benefit of prophylactic treatment is yet unknown.122 The CAR T cell therapy associated toxicity (CARTOX) working group has developed a management approach for these syndromes, based on multidisciplinary grades.123 In cytokine release syndrome, patients with grade 1 are usually managed with supportive care, those with grade 2 are managed with the anti-interleukin 6 receptor tocilizumab with or without steroids in addition to supportive care, and those with grade 3-4 are managed in the intensive care unit with aggressive supportive care, vasopressors, oxygen, tocilizumab, and steroids. Patients with grade 1 and 2 ICANS are managed supportively but an electroencephalogram is done to rule out electrical seizures and imaging of the brain to rule out edema. Patients with grade 3 and 4 ICANS need steroids and more aggressive supportive care.120

Bispecific monoclonal antibodies direct a hosts immune system (more specifically cytotoxic T cells) against cancer cells by binding CD3 on T cells with a target protein on cancer cells (fig 6).124 A type of bispecific antibody is the bispecific T cell engager (BiTE), which differs from other bispecific antibodies by containing two different single chain variable fragments connected by a linker. BiTEs often have a short half life, requiring continuous infusion to maintain efficacy.125 The first BiTE to receive FDA approval for treatment in relapsed and refractory acute lymphoblastic leukemia is Blinatumomab, a bispecific antibody that engages T cells to CD19 positive cells.126 Because BiTEs engage and activate the patients own immune cells, they have a toxicity profile similar to CAR T cells including cytokine release syndrome and ICANS.116

Structure of a bispecific antibody. BiTEs=bispecific T cell engagers

AMG 420 (previously named BI 836909) is a novel BiTE targeting BCMA on myeloma cells and CD3 on T cells, which has induced multiple myeloma cell lysis in preclinical models.127 In the first-in-human phase I study of AMG 420 in patients with at least two lines of treatment, AMG 420 was given as a continuous infusion with a pump for four week infusions, six week cycles, and a maximum of 10 cycles. The maximum tolerated dose was 400 g/day; seven (70%) of 10 patients responded to this dose. Serious adverse events were seen in 48% of patients, which were most commonly infections; and two patients had reversible grade 3 polyneuropathies. Cytokine release syndrome developed in 38% of patients, with no toxicity in the central nervous system.109 A phase Ib trial with AMG 420 is currently ongoing and although this drug looks promising, the continuous intravenous infusions present logistical challenges for patients and healthcare systems (table 2). AMG 701 is a modified version of AMG 420 (by addition of an Fc domain) with an extended half life that is suitable for dosing once a week and is being investigated in a phase I study.128

Another BCMA bispecific antibody, CC-93269, is being studied in an ongoing phase I clinical trial. This humanized 2+1, immunoglobulin G 1 based, T cell engager binds to BCMA bivalently on myeloma cells and CD3 monovalently on T cells. The bivalent binding could lead to improved potency, tumor targeting, and retention.129 All doses (range 0.15-10 mg) were given intravenously over two hours weekly for the first three cycles, every two weeks for the next three cycles, and then monthly. The most common treatment emergent adverse events of grade 3 or higher included neutropenia, anemia, and infections. Cytokine release syndrome was seen in 77% of patients, with all events developing after the first dose and less common with subsequent doses. The incidence increased with higher doses, and only one patient had cytokine release syndrome of grade 3 or higher leading to their death. In 30 patients treated, the overall response rate was 43.3% and dose dependent. The overall response rate was 88.9% in nine patients in the highest dose cohort.110

Teclistamab (JNJ-64007957) is a humanized, immunoglobulin G-4 based, bispecific DuoBody antibody that binds to BCMA and CD3 that is being studied in a phase I clinical trial. In the dose escalation part, 78 patients received doses ranging from 0.3 g/kg to 720 g/kg. The drug is given intravenously every week, with one to three step-up doses given within one week before the full dose. The overall response rate was dose dependent with no responses at doses 0.3-19.2 g/kg, 30% at 38.4-180 g/kg, and 67% at 270 g/kg. Cytokine release syndrome was seen in 56% of patients overall and 65% patients at doses over 38.4 g/kg. The most common adverse events at grade 3 or higher that were related to treatment were cytopenias and infections (table 2).111

Antibody drug conjugates are complex molecules composed of an antibody that targets cancer cells and are linked to a biologically active cytotoxic drug (known as the payload; fig 7).125 Belantamab mafodotin (GSK2857916) is a novel humanized and afucosylated (to improve antibody dependent cell mediated cytotoxicity) antibody drug conjugate that targets BCMA. It consists of an anti-BCMA monoclonal antibody conjugated to monomethyl auristatin F, a potent microtubule inhibitor.130 This antibody drug conjugate was shown to have selective myeloma cell killing in vitro and in vivo thus setting the stage for clinical trials.130131

Structure of an antibody drug conjugate

This antibody was studied in a two part phase I study. The drug was well tolerated with no dose limiting toxicities, although corneal events (such as blurry vision, dry eyes, photophobia) were seen in about 58% of patients; these events are a known toxicity of monomethyl auristatin F.132 In the dose expansion phase, 35 patients were treated, and the overall response rate was 60% with a median progression free survival 12 months.133 In a phase II, two arm study, the antibody was used in patients with relapsed and refractory multiple myeloma who had failed at least three lines of treatment. The overall response rate was 31% at the 2.5 mg/kg dose and 34% at the 3.3 mg/kg dose, which was significantly lower than the phase I study. The corneal changes or keratopathy were seen in 70% and 75% of patients, respectively. Owing to the similar response rates with the 2.5 mg/kg and 3.3 mg/kg doses and a more favorable side effect profile with the lower dose, 2.5 mg/kg will be the dose used for future studies.112 Based on these data, belantamab is the first anti-BCMA treatment to be FDA approved for relapsed and refractory multiple myeloma patients who have received four prior treatments including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

Preliminary results for another study with 18 patients treated on the belantamab, bortezomib, and dexamethasone arm was presented recently, with an overall response rate of 78%; however, all 18 patients developed grade 1-3 keratopathy.113 This visual toxicity is a unique but potentially serious side effect to this drug that needs close monitoring with an ophthalmologist. Another antibody drug conjugate, DFRF4539A, is an anti-FcRH5 (also known as FcRL5) antibody conjugated to monomethyl auristatin and has shown limited activity and high incidence of toxicity in a phase I study; therefore, it was unsuccessful for this disease (table 2).134135

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Mesenchymal stem cells in cardiac regeneration: a detailed ...

KENILWORTH, N.J.--(BUSINESS WIRE)--Sep 20, 2020--

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the presentation of new data for three investigational medicines in Mercks diverse and expansive oncology pipeline: vibostolimab (MK-7684), an anti-TIGIT therapy; MK-4830, a first-in-class anti-ILT4 therapy; and MK-6482, an oral HIF-2 inhibitor. Data from cohort expansions of a Phase 1b trial evaluating vibostolimab, as monotherapy and in combination with KEYTRUDA, Mercks anti-PD-1 therapy, in patients with metastatic non-small cell lung cancer (NSCLC; Abstract #1410P and Abstract #1400P), and first-time Phase 1 data for MK-4830 in patients with advanced solid tumors (Abstract #524O), demonstrated acceptable safety profiles for these two investigational medicines and early signals of anti-tumor activity. Additionally, late-breaking Phase 2 data for MK-6482 showed anti-tumor responses in von Hippel-Lindau (VHL) disease patients with clear cell renal cell carcinoma (RCC) and other tumors (Abstract #LBA26).

The new data for these three investigational medicines are encouraging and highlight continued momentum in our rapidly expanding oncology pipeline, Dr. Eric H. Rubin, senior vice president, early-stage development, clinical oncology, Merck Research Laboratories. Over the past five years, KEYTRUDA has become foundational in the treatment of certain advanced cancers. Our broad oncology portfolio and promising pipeline candidates are a testament to our commitment to bring forward innovative new medicines to address unmet medical needs in cancer care.

Vibostolimab (Anti-TIGIT Therapy): Early Findings in Metastatic NSCLC (Abstract #1410P and Abstract #1400P)

Vibostolimab in combination with KEYTRUDA was evaluated in patients with metastatic NSCLC who had not previously received antiPD-1/PD-L1 therapy, but the majority of whom had received > 1 prior lines of therapy (73%, n=30/41) in Abstract #1410P. In Part B of the first-in-human, open-label, Phase 1 trial ( NCT02964013 ) all patients received vibostolimab (200 or 210 mg) in combination with KEYTRUDA (200 mg) on Day 1 of each three-week cycle for up to 35 cycles. The primary endpoints of the study were safety and tolerability. Secondary endpoints included objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS) based on investigator review per RECIST v1.1. In this anti-PD-1/PD-L1 nave study, vibostolimab in combination with KEYTRUDA had a manageable safety profile and demonstrated promising anti-tumor activity. Treatment-related adverse events (TRAEs) with vibostolimab in combination with KEYTRUDA occurred in 34 patients (83%). The most frequent TRAEs (20%) were pruritus (34%), hypoalbuminemia (29%) and pyrexia (20%). Grade 3-5 TRAEs occurred in six patients (15%). No deaths due to TRAEs occurred. Across all patients enrolled, treatment with vibostolimab in combination with KEYTRUDA demonstrated an ORR of 29% (95% CI, 16-46) and median PFS was 5.4 months (95% CI, 2.1-8.2). The median DOR was not reached (range, 4 to 17+ months). Among patients whose tumors express PD-L1 (tumor proportion score [TPS] 1%) (n=13), the ORR was 46% (95% CI, 19-75) and median PFS was 8.4 months (95% CI, 3.9-10.2). Among patients whose tumors express PD-L1 (TPS <1%) (n=12), the ORR was 25% (95% CI, 6-57), and median PFS was 4.1 months (95% CI, 1.9-not reached [NR]). PD-L1 status was not available for 16 patients. Median follow-up for the study was 11 months (range, 7 to 18).

Additional data from a separate cohort of the same Phase 1b trial evaluated vibostolimab as monotherapy (n=41) and in combination with KEYTRUDA (n=38) in patients with metastatic NSCLC whose disease progressed on prior anti-PD-1/PD-L1 therapy (Abstract #1400P). In the study, 78% of patients had received > 2 lines of prior therapy. In the study, patients received vibostolimab monotherapy (200 or 210 mg) or vibostolimab (200 or 210 mg) in combination with KEYTRUDA (200 mg) on Day 1 of each three-week cycle for up to 35 cycles. The primary endpoints of the study were safety and tolerability. Secondary endpoints included ORR and DOR. Vibostolimab as monotherapy or in combination with KEYTRUDA had a manageable safety profile and demonstrated modest anti-tumor activity in patients whose disease was refractory to PD-1/PD-L1 inhibition, most of whom had previously received several lines of therapy for advanced disease prior to enrollment. Grade 3-5 TRAEs occurred in 15% of patients receiving vibostolimab monotherapy and 13% of patients receiving vibostolimab in combination with KEYTRUDA. The most common TRAEs (10% in either arm) were pruritus, fatigue, rash, arthralgia and decreased appetite. One patient died due to treatment-related pneumonitis in the vibostolimab and KEYTRUDA combination arm. The ORR was 7% (95% CI, 2-20) with vibostolimab monotherapy and 5% (95% CI, <1-18) with vibostolimab in combination with KEYTRUDA. The median DOR was 9 months (range, 9 to 9) with vibostolimab monotherapy and 13 months (range, 4+ to 13) with vibostolimab in combination with KEYTRUDA.

Data from these cohort expansion studies are encouraging and support the continued development of vibostolimab, which is being evaluated alone and in combination with KEYTRUDA across multiple solid tumors, including NSCLC and melanoma. In the ongoing Phase 2 KEYNOTE-U01 umbrella study ( NCT04165798 ), substudy KEYNOTE-01A ( NCT04165070 ) is evaluating vibostolimab in combination with KEYTRUDA plus chemotherapy for the first-line treatment of patients with advanced NSCLC who had not received prior treatment with an anti-PD-1/PD-L1. Merck plans to initiate a Phase 3 study of vibostolimab in NSCLC in the first half of 2021. Ongoing trials in melanoma include the Phase 1/2 KEYNOTE-U02 umbrella study comprised of three substudies evaluating vibostolimab in combination with KEYTRUDA across treatment settings (substudy 02A: NCT04305041, substudy 02B: NCT04305054 and substudy 02C: NCT04303169 ).

MK-4830 (Anti-ILT4 Therapy): Initial Results in Advanced Solid Tumors (Abstract #524O)

In this first-in-human Phase 1, open-label, multi-arm, multi-center, dose escalation study ( NCT03564691 ), MK-4830, Mercks first-in-class anti-ILT4 therapy, was evaluated as monotherapy (n=50) and in combination with KEYTRUDA (n=34) in patients with advanced solid tumors. The majority of patients enrolled in the study (51%) had received three or more prior lines of therapy. MK-4830 was administered intravenously at escalating doses every three weeks alone or in combination with KEYTRUDA (200 mg every three weeks). The primary endpoints of the dose escalation part of the study were safety and tolerability; Pharmacokinetics was a secondary endpoint, and exploratory objectives included ORR per RECIST v1.1, evaluation of receptor occupancy and immune correlates of response in blood and tumor.

Findings showed that MK-4830 as monotherapy and in combination with KEYTRUDA had an acceptable safety profile and demonstrated dose-related evidence of target engagement in patients with advanced solid tumors. No dose-limiting toxicities were observed; the maximum-tolerated dose was not reached. Any-grade adverse events were consistent with those associated with KEYTRUDA. Treatment-related AEs occurred in 54% (n=28/52) of patients who received MK-4830 in combination with KEYTRUDA and 48% (n=24/50) of patients who received MK-4830 monotherapy; the majority were Grade 1 and 2. Preliminary efficacy data showed an ORR of 24% (n=8/34) in patients who received MK-4830 in combination with KEYTRUDA. All responses occurred in heavily pretreated patients, including five who had progressed on prior anti-PD-1 therapy (n=5/11). Some patients received more than one year of treatment, and treatment is ongoing in several patients.

These early data support the continued development of MK-4830 in combination with KEYTRUDA in patients with advanced solid tumors. Expansion cohorts of this study include pancreatic adenocarcinoma, glioblastoma, head and neck squamous cell carcinoma (recurrent or metastatic; PD-L1 positive), advanced NSCLC and gastric cancer.

MK-6482 (HIF-2 Inhibitor): Results in VHL-Associated RCC and Non-RCC Tumors (Abstract #LBA26)

In this Phase 2, open-label, single-arm trial, MK-6482 was evaluated for the treatment of VHL-associated RCC ( NCT03401788 ). New data include findings for MK-6482 in VHL patients with non-RCC tumors and updated data in VHL patients with RCC. First-time data in VHL-associated RCC were presented in the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting. The study enrolled adult patients with a pathogenic germline VHL variation, measurable localized or non-metastatic RCC, no prior systemic anti-cancer therapy, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients received MK-6482 120 mg orally once daily until disease progression, unacceptable toxicity, or investigators or patients decision to withdraw. The primary endpoint was ORR of VHL-associated RCC tumors per RECIST v1.1 by independent radiology review. Secondary endpoints included DOR, time to response, PFS, efficacy in non-RCC tumors, and safety and tolerability.

Promising clinical activity continues to be observed with MK-6482 in treatment-nave patients with VHL-associated RCC. Among 61 patients, results showed a confirmed ORR of 36.1% (95% CI, 24.2-49.4); all responses were partial responses, and 38% of patients had stable disease. The median time to response was 31.1 weeks (range, 11.9 to 62.3), and median DOR was not yet reached (range, 11.9 to 62.3 weeks). Additionally, 91.8% (n=56) of patients had a decrease in size of target lesions. Median PFS has not been reached, and the PFS rate at 52 weeks was 98.3%. Median duration of treatment was 68.7 weeks (range, 18.3 to 104.7), and 91.8% of patients were still on therapy after a minimum follow-up of 60 weeks.

In patients with non-RCC tumors, results in those with pancreatic lesions (n=61) showed a confirmed ORR of 63.9% (95% CI, 50.6-75.8), with four complete responses and 35 partial responses. Additionally, 34.4% had stable disease. In those with central nervous system (CNS) hemangioblastoma (n=43), results showed a confirmed ORR of 30.2% (95% CI, 17.2-46.1), with five complete responses and eight partial responses. Additionally, 65.1% had stable disease. In patients with retinal lesions (n=16), 93.8% of patients had improved or stable response.

In this Phase 2 study, TRAEs occurred in 98.4% of patients, and there were no Grade 4-5 TRAEs. The most common all-cause adverse events (20%) were anemia (90.2%), fatigue (60.7%), headache (37.7%), dizziness (36.1%) and nausea (31.1%). Grade 3 all-cause adverse events included anemia (6.6%), fatigue (4.9%) and dyspnea (1.6%). One patient discontinued treatment due to a TRAE (Grade 1 dizziness).

As announced, data spanning more than 15 types of cancer will be presented from Mercks broad oncology portfolio and investigational pipeline at the congress. A compendium of presentations and posters of Merck-led studies is available here. Follow Merck on Twitter via @Merck and keep up to date with ESMO news and updates by using the hashtag #ESMO20.

About Vibostolimab

Vibostolimab is an anti-TIGIT therapy discovered and developed by Merck. Vibostolimab binds to TIGIT and blocks the interaction between TIGIT and its ligands (CD112 and CD155), thereby activating T lymphocytes which help to destroy tumor cells. The effect of combining KEYTRUDA with vibostolimab blocking both the TIGIT and PD-1 pathways simultaneously is currently being evaluated across multiple solid tumors, including NSCLC and melanoma.

About MK-4830

MK-4830 is a novel antibody directed against the inhibitory immune checkpoint receptor immunoglobulin-like transcript 4 (ILT4). Unlike current T cell-targeted antibodies (e.g., anti-PD1, anti-CTLA-4), anti-ILT4 is believed to attenuate immunosuppression imposed by tolerogenic myeloid cells in the tumor microenvironment. MK-4830 is currently being evaluated alone and in combination with KEYTRUDA across multiple solid tumors as part of ongoing Phase 1 and 2 trials.

About MK-6482

MK-6482 is an investigational, novel, potent, selective, oral HIF-2 inhibitor that is currently being evaluated in a Phase 3 trial in advanced RCC ( NCT04195750 ), a Phase 2 trial in VHL-associated RCC ( NCT03401788 ), and a Phase 1/2 dose-escalation and dose-expansion trial in advanced solid tumors, including advanced RCC ( NCT02974738 ). Proteins known as hypoxia-inducible factors, including HIF-2, can accumulate in patients when VHL, a tumor-suppressor protein, is inactivated. The accumulation of HIF-2 can lead to the formation of both benign and malignant tumors. This inactivation of VHL has been observed in more than 90% of RCC tumors. Research into VHL biology that led to the discovery of HIF-2 was awarded the Nobel Prize in Physiology or Medicine in 2019.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

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

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

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

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

Non-Small Cell Lung Cancer

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

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

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

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

Small Cell Lung Cancer

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

Head and Neck Squamous Cell Cancer

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

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

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

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

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

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

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

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

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

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

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

Gastric Cancer

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

Esophageal Cancer

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

Cervical Cancer

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

Hepatocellular Carcinoma

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

Merkel Cell Carcinoma

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

Renal Cell Carcinoma

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

Tumor Mutational Burden-High

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

Cutaneous Squamous Cell Carcinoma

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

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

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

Embryofetal Toxicity

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Merck Presents Promising New Data for Three Investigational Medicines From Diverse and Expansive Oncology Pipeline at ESMO Virtual Congress 2020 - The...

NEW YORK, Sept. 15, 2020 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in allogeneic cellular medicines for inflammatory diseases, today announced that its lead product candidate remestemcel-L has been selected as the winner of the Fierce Innovation Awards - Life Sciences Edition 2020 for Biotech Innovation.The Fierce Innovation Awards is a peer-reviewed program from the publisher ofFierceBiotech and FiercePharma.

Mesoblast Chief Executive Dr Silviu Itescu stated: This important award is recognition of Mesoblasts leadership as an innovator in the cell therapy industry, and of the potential for remestemcel-L to profoundly impact the lives of children suffering with steroid-refractory acute graft versus host disease (SR-aGVHD).

Remestemcel-L is under priority review by the United States Food and Drug Administration (FDA) for pediatric SR-aGVHD and, if approved, product launch in the United States is expected in 2020. The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of September 30, 2020.

Remestemcel-L is an investigational therapy comprising culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor. It is thought to have immunomodulatory properties to counteract the cytokine storms that are implicated in various inflammatory conditions by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

Given the extensive inflammatory response in COVID-19 infection, remestemcel-L is also being evaluated in a randomized, controlled Phase 3 trial in up to 300 ventilator-dependent adults with moderate to severe acute respiratory distress syndrome (ARDS), the primary cause of mortality in COVID-19 patients. The trial aims to confirm results from a pilot study at New Yorks Mt Sinai hospital which showed that nine of 12 patients (75%) were successfully discharged from hospital a median of 10 days after receiving two intravenous doses of remestemcel-L within five days.The trials independent Data Safety Monitoring Board (DSMB) recently completed an interim analysis of the trials first 30% enrolled patients and recommended that the trial should continue as planned after reviewing all safety data and results for the trials primary endpoint of all-cause mortality within 30 days of randomization.The DSMB will perform a second interim analysis when 45% of the enrollment target has completed 30 days of follow-up. About Fierce Innovation Awards Life Sciences Edition 2020These awards highlight companies that demonstrate innovative solutions, technologies, and services that have the potential to make the greatest impact for biotech and pharma companies.The evaluation criteria are effectiveness, technical innovation, competitive advantage, financial impact, and true innovation.The awards programs applications were reviewed by a panel of executives from majorbiotech and pharmacompanies includingAstellas, Accenture, AstraZeneca, Angiocrine Bioscience, Biotech Research Group, NIHR Clinical Research Network, Medidata Solutions and PPD.

About MesoblastMesoblast Limited (Nasdaq:MESO; ASX:MSB) is a world leader in developing allogeneic (off-the-shelf) cellular medicines. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of commercial products and late-stage product candidates. Mesoblast has a strong and extensive global intellectual property (IP) portfolio with protection extending through to at least 2040 in all major markets. The Companys proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblasts Biologics License Application to seek approval of its product candidate RYONCIL (remestemcel-L) for pediatric steroid-refractory acute graft versus host disease has been accepted for priority review by the United States Food and Drug Administration (FDA), and if approved, product launch in the United States is expected in 2020. Remestemcel-L is also being developed for other inflammatory diseases in children and adults including moderate to severe acute respiratory distress syndrome (ARDS). Mesoblast is completing Phase 3 trials for its product candidates for advanced heart failure and chronic low back pain. Two products have been commercialized in Japan and Europe by Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

Forward-Looking StatementsThis announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward-looking statements include, but are not limited to, statements about: the timing, progress and results of Mesoblasts preclinical and clinical studies; Mesoblasts ability to advance product candidates into, enroll and successfully complete, clinical studies; the timing or likelihood of regulatory filings and approvals; and the pricing and reimbursement of Mesoblasts product candidates, if approved; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

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Mesoblast Wins 2020 Fierce Biotech Innovation of the Year Award for remestemcel-L - GlobeNewswire

Sept. 9, 2020 12:00 UTC

ALAMEDA, Calif. & CARLSBAD, Calif.--(BUSINESS WIRE)-- AgeX Therapeutics, Inc.(AgeX: NYSE American: AGE), a company focused on developing and commercializing innovative therapeutics for human aging, and Lineage Cell Therapeutics, Inc.. (Lineage: NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs, and ES Cell International Pte Ltd. (ESI), a subsidiary of Lineage, today announced the broadening of their collaborative relationship with regard to ESI stem cell lines. ESI cell lines are current Good Manufacturing Practice (cGMP)-compatible, registered with the National Institutes of Health (NIH), and widely studied as a potential source for the industrial-scale manufacture of any cell type in the human body. Neither party made or received any cash payments in connection with this arrangement.

Both Lineage and AgeX are pioneering important aspects of regenerative medicine. Working together, we have amended our agreement regarding ESI cell lines derived under cGMP to be optimal for the business needs of each company, stated Brian M. Culley, Lineages CEO. In particular, Lineage has acquired exclusivity for the use of ESI cell lines in spinal cord injury and certain oncology indications. On the other hand, AgeX has gained greater flexibility and independence to support its efforts toward licensing certain technologies and cell lines to third parties. With this step complete, we next intend to explore additional opportunities to collaborate with AgeX on promising tissue regenerating projects.

The ESI cell lines are recognized for being the first clinical-grade human pluripotent stem cell lines created under cGMP as described in the publication Cell Stem Cell (2007;1:490-4). It may become possible to generate potentially limitless quantities of all the cell types of the human body from these master cell banks with a wide array of potential therapeutic applications. These cell lines are listed on the NIH Stem Cell Registry and are among the best characterized and documented stem cell lines available globally. Importantly, ESI cells are among only a few pluripotent stem cell lines from which a derived cell therapy product candidate has been granted FDA investigational new drug (IND) clearance to commence human studies.

Key to the creation of shareholder value is the placement of these important assets in the hands of collaborators to advance the development of a vast number of regenerative therapies, said Michael West, Ph.D., AgeXs CEO. Our collaborative relationship with Lineage led to this streamlined process that may facilitate the commercialization of these applications to the benefit of shareholders of each company. Since the beginning of the year, AgeX has entered into new research and commercial arrangements utilizing an array of its technology platforms, such as UniverCyteTM for the engineering of universally transplantable cells, PureStem for the manufacture and derivation of cells, and an ESI cell line as source material for deriving cellular therapeutics.

About AgeX Therapeutics, Inc

AgeX Therapeutics, Inc. (NYSE American: AGE) is focused on developing and commercializing innovative therapeutics for human aging. Its PureStem and UniverCyte manufacturing and immunotolerance technologies are designed to work together to generate highly defined, universal, allogeneic, off-the-shelf pluripotent stem cell-derived young cells of any type for application in a variety of diseases with a high unmet medical need. AgeX has two preclinical cell therapy programs: AGEX-VASC1 (vascular progenitor cells) for tissue ischemia and AGEX-BAT1 (brown fat cells) for Type II diabetes. AgeXs revolutionary longevity platform induced Tissue Regeneration (iTR) aims to unlock cellular immortality and regenerative capacity to reverse age-related changes within tissues. AGEX-iTR1547 is an iTR-based formulation in preclinical development. HyStem is AgeXs delivery technology to stably engraft PureStem cell therapies in the body. AgeXs core product pipeline is intended to extend human healthspan. AgeX is seeking opportunities to establish licensing and collaboration arrangements around its broad IP estate and proprietary technology platforms and therapy product candidates. For more information, please visit http://www.agexinc.com or connect with the company on Twitter, LinkedIn, Facebook, and YouTube.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include three allogeneic (off-the-shelf) product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, a leading cause of blindness in the developed world; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; and (iii) VAC, an allogeneic dendritic cell therapy platform for immuno-oncology and infectious disease, currently in clinical development for the treatment of non-small cell lung cancer and in preclinical development for additional cancers and as a vaccine against infectious diseases, including SARS-CoV-2, the virus which causes COVID-19. For more information, please visit http://www.lineagecell.com or follow the Company on Twitter @LineageCell.

About ESI

ES Cell International Pte Ltd (ESI). Established in 2000, ESI, a wholly owned subsidiary of Lineage Cell Therapeutics, Inc., developed ESI hESC lines in compliance with the principles of current Good Manufacturing Practices and has made them available to various biopharmaceutical companies, universities and other research institutions, including AgeX. These ESI cell lines are extensively characterized and most of the lines have documented and publicly available genomic sequences.

Forward-Looking Statements for AgeX

Certain statements contained in this release are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Any statements that are not historical fact including, but not limited to statements that contain words such as will, believes, plans, anticipates, expects, estimates should also be considered forward-looking statements. Forward-looking statements involve risks and uncertainties. Without limitation, such risks include those associated with the use of human pluripotent stem cell lines in the research, development, and use of therapies for the treatment of human diseases, disorders, and injuries, and risks associated with commercializing the pluripotent stem cell lines. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the business of AgeX Therapeutics, Inc. and its respective subsidiaries, particularly those mentioned in the cautionary statements found in more detail in the Risk Factors section of its most recent Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commissions (copies of which may be obtained at http://www.sec.gov). Subsequent events and developments may cause these forward-looking statements to change. Undue reliance should not be placed on forward-looking statements, which speak only as of the date on which they were made. AgeX specifically disclaims any obligation or intention to update or revise these forward-looking statements as a result of changed events or circumstances that occur after the date of this release, except as required by applicable law.

Forward-Looking Statements for Lineage

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as believe, may, will, estimate, continue, anticipate, design, intend, expect, could, plan, potential, predict, seek, should, would, contemplate, project, target, tend to, or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the potential commercialization of ESI cell lines. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineages actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including risks and uncertainties inherent in Lineages business and other risks in Lineages filings with the Securities and Exchange Commission (the SEC). Lineages forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading Risk Factors in Lineages periodic reports with the SEC, including Lineages Annual Report on Form 10-K filed with the SEC on March 12, 2020 and its other reports, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200909005398/en/

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AgeX Therapeutics and Lineage Cell Therapeutics Announce Expansion of Agreement Related to ESI Clinical-grade Pluripotent Stem Cell Lines for...

AgeX Therapeutics, Inc. (AgeX: NYSE American: AGE), a company focused on developing and commercializing innovative therapeutics for human aging, and Lineage Cell Therapeutics, Inc. (Lineage: NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs, and ES Cell International Pte Ltd. (ESI), a subsidiary of Lineage, today announced the broadening of their collaborative relationship with regard to ESI stem cell lines. ESI cell lines are current Good Manufacturing Practice (cGMP)-compatible, registered with the National Institutes of Health (NIH), and widely studied as a potential source for the industrial-scale manufacture of any cell type in the human body. Neither party made or received any cash payments in connection with this arrangement.

Both Lineage and AgeX are pioneering important aspects of regenerative medicine. Working together, we have amended our agreement regarding ESI cell lines derived under cGMP to be optimal for the business needs of each company, stated Brian M. Culley, Lineages CEO. In particular, Lineage has acquired exclusivity for the use of ESI cell lines in spinal cord injury and certain oncology indications. On the other hand, AgeX has gained greater flexibility and independence to support its efforts toward licensing certain technologies and cell lines to third parties. With this step complete, we next intend to explore additional opportunities to collaborate with AgeX on promising tissue regenerating projects.

The ESI cell lines are recognized for being the first clinical-grade human pluripotent stem cell lines created under cGMP as described in the publication Cell Stem Cell (2007;1:490-4). It may become possible to generate potentially limitless quantities of all the cell types of the human body from these master cell banks with a wide array of potential therapeutic applications. These cell lines are listed on the NIH Stem Cell Registry and are among the best characterized and documented stem cell lines available globally. Importantly, ESI cells are among only a few pluripotent stem cell lines from which a derived cell therapy product candidate has been granted FDA investigational new drug (IND) clearance to commence human studies.

Key to the creation of shareholder value is the placement of these important assets in the hands of collaborators to advance the development of a vast number of regenerative therapies, said Michael West, Ph.D., AgeXs CEO. Our collaborative relationship with Lineage led to this streamlined process that may facilitate the commercialization of these applications to the benefit of shareholders of each company. Since the beginning of the year, AgeX has entered into new research and commercial arrangements utilizing an array of its technology platforms, such as UniverCyteTM for the engineering of universally transplantable cells, PureStem for the manufacture and derivation of cells, and an ESI cell line as source material for deriving cellular therapeutics.

About AgeX Therapeutics, Inc

AgeX Therapeutics, Inc. (NYSE American: AGE) is focused on developing and commercializing innovative therapeutics for human aging. Its PureStem and UniverCyte manufacturing and immunotolerance technologies are designed to work together to generate highly defined, universal, allogeneic, off-the-shelf pluripotent stem cell-derived young cells of any type for application in a variety of diseases with a high unmet medical need. AgeX has two preclinical cell therapy programs: AGEX-VASC1 (vascular progenitor cells) for tissue ischemia and AGEX-BAT1 (brown fat cells) for Type II diabetes. AgeXs revolutionary longevity platform induced Tissue Regeneration (iTR) aims to unlock cellular immortality and regenerative capacity to reverse age-related changes within tissues. AGEX-iTR1547 is an iTR-based formulation in preclinical development. HyStem is AgeXs delivery technology to stably engraft PureStem cell therapies in the body. AgeXs core product pipeline is intended to extend human healthspan. AgeX is seeking opportunities to establish licensing and collaboration arrangements around its broad IP estate and proprietary technology platforms and therapy product candidates. For more information, please visit http://www.agexinc.com or connect with the company on Twitter, LinkedIn, Facebook, and YouTube.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include three allogeneic (off-the-shelf) product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, a leading cause of blindness in the developed world; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; and (iii) VAC, an allogeneic dendritic cell therapy platform for immuno-oncology and infectious disease, currently in clinical development for the treatment of non-small cell lung cancer and in preclinical development for additional cancers and as a vaccine against infectious diseases, including SARS-CoV-2, the virus which causes COVID-19. For more information, please visit http://www.lineagecell.com or follow the Company on Twitter @LineageCell.

About ESI

ES Cell International Pte Ltd (ESI). Established in 2000, ESI, a wholly owned subsidiary of Lineage Cell Therapeutics, Inc., developed ESI hESC lines in compliance with the principles of current Good Manufacturing Practices and has made them available to various biopharmaceutical companies, universities and other research institutions, including AgeX. These ESI cell lines are extensively characterized and most of the lines have documented and publicly available genomic sequences.

Forward-Looking Statements for AgeX

Certain statements contained in this release are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Any statements that are not historical fact including, but not limited to statements that contain words such as will, believes, plans, anticipates, expects, estimates should also be considered forward-looking statements. Forward-looking statements involve risks and uncertainties. Without limitation, such risks include those associated with the use of human pluripotent stem cell lines in the research, development, and use of therapies for the treatment of human diseases, disorders, and injuries, and risks associated with commercializing the pluripotent stem cell lines. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the business of AgeX Therapeutics, Inc. and its respective subsidiaries, particularly those mentioned in the cautionary statements found in more detail in the Risk Factors section of its most recent Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commissions (copies of which may be obtained at http://www.sec.gov). Subsequent events and developments may cause these forward-looking statements to change. Undue reliance should not be placed on forward-looking statements, which speak only as of the date on which they were made. AgeX specifically disclaims any obligation or intention to update or revise these forward-looking statements as a result of changed events or circumstances that occur after the date of this release, except as required by applicable law.

Forward-Looking Statements for Lineage

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as believe, may, will, estimate, continue, anticipate, design, intend, expect, could, plan, potential, predict, seek, should, would, contemplate, project, target, tend to, or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the potential commercialization of ESI cell lines. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineages actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including risks and uncertainties inherent in Lineages business and other risks in Lineages filings with the Securities and Exchange Commission (the SEC). Lineages forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading Risk Factors in Lineages periodic reports with the SEC, including Lineages Annual Report on Form 10-K filed with the SEC on March 12, 2020 and its other reports, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200909005398/en/

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Lineage Cell Therapeutics : AgeX Therapeutics and Lineage Cell Therapeutics Announce Expansion of Agreement Related to ESI Clinical-grade Pluripotent...

Concerning heart failure (HF), the current COVID-19 pandemic is having a dramatic effect on the daily life of each individual, ranging from social distancing measures applied in most countries to getting severely diseased due to the virus. Cardiovascular Disease (CVD) is among the most common conditions in people that die of the infection. The burden of CVD accounts for over 60 million people in the EU alone, therefore, it is the leading cause of death in the world.

Although COVID-19 shows us the direct impact of a potential treatment for peoples health, CVD is a stealthy pandemic killer. HF is a chronic disease condition in which the heart is not able to fill properly or efficiently pump blood throughout your body, caused by different stress conditions including myocardial infarction, atherosclerosis, diabetes and high blood pressure. Several measures are commonly used to treat heart disease, such as lifestyle changes and medications like beta-blockers and ACE inhibitors, yet these typically only slow down the progression of the disease.

Biomedical research is exploring new avenues by combining scientific insights with new technologies to overcome chronic diseases like HF. Among the most appealing and promising technologies are the use of cardiac tissue engineering and extracellular vesicles-mediated repair strategies.

Upon an initial cell loss post-infarction, it is appealing to replace this massive loss in contractile cells for new cells and thereby not treating patients symptoms, but repairing the cause of the disease. Cardiac cell therapy has been pursued for many years with variable results in small initial trials upon injection into patients. Different cell types have been used to help the myocardium in need, but the most promising approaches aim to use induced pluripotent cells (iPS) from reprogrammed cells from the patient themselves that can be directed towards contractile myocardial cells. These cells in combination with natural materials, in which the cells are embedded in the heart, can be used for tissue engineering strategies (1). Together with different international partners, Sluijters team are trying to develop strategies to use these iPS-derived contractile cells for myocardial repair via direct myocardial injection (H2020-Technobeat-66724) or to make a scaffold that can be used as a personalised biological ventricular assist device (H2020-BRAV-874827). A combination of engineering and biology to mimic the native myocardium aims to replace the chronically ill tissue for healthy and well-coupled heart tissue that can enhance the contractile performance of the heart.

Recently, a Dutch national programme started, called RegMedXB, in which the reparative treatment of the heart is aimed to be performed outside the patients body. During the time the heart is outside the body; the patient is connected to the heart-lung machine, and after restoring function, it will be re-implanted. The so-called Cardiovascular Moonshot aims to create a therapy that best suits the individual patient, by having their heart beating in a bioreactor, outside the body. Although it sounds very futuristic, many small lessons will be learned to feet novel therapeutic insights.

The initial injection of stem cells did result in a nice improvement of myocardial performance. We have now learned that rather than these delivered cells helping the heart themselves, the release of small lipid carriers called extracellular vesicles (EVs) (2) from these cells occur. These EVs carry different biological molecules, including nucleotides, proteins and lipids, and are considered to be the bodies nanosized messengers for communication. The use of stem cell-derived EVs are now being explored as a powerful means to change the course of the disease. Via these small messengers, natural biologics are delivered to diseased cells and thereby help them to overcome the stressful circumstances. EVs carry reparative signals that can be transferred to the diseased heart and thereby change the course of heart disease in some patients.

Within the EVICARE program (3) (H2020-ERC-725229), Sluijters team are using stem cell-derived EVs to change the response of the heart to injury. Also, to understand which heart cells and processes are being affected, they use materials to facilitate a slow release of biomaterials over an extended period rather than a single dose, which is probably essential for a chronic disease like HF. For now, improved blood flow is the main aim but the team have seen other effects as well, such as cardiovascular cell proliferation (4) by which the heart cells themselves start to repair the organ.

The use of EVs basically aims to enhance the endogenous repair mechanisms of the heart. These natural carriers can be mimicked with synthetic materials, or used as a hybrid of the two, thereby creating an engineered nanoparticle, that is superior in the intracellular delivery of genetic materials. The possibility of loading different biological materials allows a further tuning of its effectiveness and use in different disease conditions, creating a new off-the-shelf delivery system for nanomedicine to treat cancer and CVD (H2020-Expert-825828).

As is true of the current COVID-19 pandemic, HF is also a growing chronic disease that affects millions of people worldwide. The chronic damaged myocardium needs reparative strategies in the future to lower the social burden for patients, but also to keep the economic consequences affordable. New scientific insights with cutting edge technological developments will help to address these needs of CVD patients and their families.

References

(1) Madonna R, Van Laake LW, Botker HE, Davidson SM, De Caterina R, Engel FB, Eschenhagen T, Fernandez-Aviles F, Hausenloy DJ, Hulot JS, Lecour S, Leor J, Menasch P, Pesce M, Perrino C, Prunier F, Van Linthout S, Ytrehus K, Zimmermann WH, Ferdinandy P, Sluijter JPG. ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure. Cardiovasc Res. 2019 Mar 1;115(3):488-500.

(2) Sluijter JPG, Davidson SM, Boulanger, CM, Buzs EI, de Kleijn DPV, Engel FB, Giricz Z, Hausenloy DJ, Kishore R, Lecour S, Leor J, Madonna R, Perrino C, Prunier F, Sahoo S, Schiffelers RM, Schulz R, Van Laake LW, Ytrehus K, Ferdinandy P. Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res. 2018 Jan 1;114(1):19-34.

(3) https://www.sluijterlab.com/extracellular-vesicle-inspired-ther

(4) Maring JA, Lodder K, Mol E, Verhage V, Wiesmeijer KC, Dingenouts CKE, Moerkamp AT, Deddens JC, Vader P, Smits, AM, Sluijter JPG, Goumans MJ. Cardiac Progenitor Cell-Derived Extracellular Vesicles Reduce Infarct Size and Associate with Increased Cardiovascular Cell Proliferation. J Cardiovasc Transl Res. 2019 Feb;12(1):5-17.

Please note: this is a commercial profile.

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Innovative treatments for heart failure - Open Access Government