Cytokines TNF and IL-6 can cause severely damaging inflammatory effects as a result of stem cells attacking host cells of blood cancer patients

By BRANDON NGUYEN science@theaggie.org

Researchers at the UC Davis Medical Center recently discovered a novel treatment against graft-versus-host disease (GVHD), a potentially lethal inflammatory condition that can arise following stem cell transplantation, which treats blood cancers and disorders. Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) to treat some blood cancers and disorders involves injecting a donors bone marrow stem cells, also known as graft, into blood cancer patients undergoing chemotherapy and radiation therapy.

Dr. William Murphy, a professor at the UC Davis School of Medicine under the Department of Dermatology and Internal Medicine and senior author of the study, further explained what GVHD is under the context of blood cancers.

If we take stem cells from another source, usually trying to match as much as we can from a related source such as a sibling, there seems to be an anti-tumor effect, Murphy said. This desired, beneficial effect from stem cell transplantation is called the graft-versus-tumor (GVT) effect. But the graft-versus-host disease means those immune cells can also attack not just the cancer, but the recipient or patient, which occurs pretty often.

The medical dilemma Murphy and his team of researchers faced involved maximizing GVT effects while minimizing GVHD during stem cell treatment to help the patient effectively fight off the tumor. Logan Vick, a graduate student under Murphys lab at the UC Davis Medical Center and a co-author of the study, talked about the major findings that help minimize GVHD in allo-HSCT patients.

In graft-versus-host disease, something that can be picked up as a symptom is this release of cytokines, which are inflammatory proteins, Vick said. TNF and IL-6, which are two inflammatory cytokines, are often used as tools of the immune system to combat either viruses or different pathogens, but prolonged inflammation can have consequences. So by blocking these two cytokines, what we call a dual cytokine blockade, can help ameliorate GVHD.

The cytokines, TNF and IL-6, that Vick focuses on can cause a cytokine storm, which can occur during GVHD when donor immune stem cells attack the hosts healthy cells instead of the tumor and induce inflammation caused by cytokines. GVHD and the dangerous cytokine storm effect has been a problem for stem cell transplantation treatments, but Murphys team of researchers have just found a potential cure to GVHD while still maintaining the efficacy of the treatment.

Lam T. Khuat, a postdoctoral researcher at Murphys lab and the first author of the study, summarized the beneficial results from dual cytokine blockage.

Many treatments for GVHD involve suppressing the bodys immunity, which can inhibit beneficial GVT effects, Khuat said via email. For this reason, it was important to determine if blocking these cytokines impacted the GVT response. Fortunately, anti-tumor effects remained after the transplant and with the combined intervention.

Clinical methods have often employed single cytokine blockades; however, with the novel finding that dual cytokine blockades can minimize the proinflammatory responses induced by GVHD, the treatment can also be applied in other health conditions that require stem cell transplantation or reducing inflammatory side effects.

Normally, when you have an overactive immune system, whether its autoimmune disorders or GVHD or even in viral infections, the treatments sometimes blanket immunosuppression with steroids, Murphy said. Well, that works because they turn off the immune system, but in the case of cancer and viral infections, you want a working immune system. The beauty of using this double block, which can be applied in other clinical settings, is it doesnt suppress the immune system while preventing the inflammation and the damage.

Written by: Brandon Nguyen science@theaggie.org

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UC Davis researchers find dual cytokine blockage as a novel treatment against graft-versus-host disease in blood stem cell transplantations - The...

Building on its education, research and public outreach achievements over the past 55 years, including groundbreaking work in response to the COVID-19 pandemic, the University of Arizona Health Sciences is launching several new initiatives in 2022 to address critical statewide, national and global health care needs.

Under its Tomorrow is here focus, UArizona Health Sciences is establishing new research centers and education programs to amplify the impact of its strategic initiatives that are advancing Next-Generation Education, Precision Health Care for All, Innovations in Healthy Aging, Building Defenses Against Disease and New Frontiers for Better Health.

As one of the leading academic medical centers in the southwestern United States, and building on the strengths we have developed over the course of the pandemic, the University of Arizona Health Sciences has unprecedented opportunities to excel in education, research and outreach in more and better ways than ever before, said Michael D. Dake, MD, UArizona Health Sciences senior vice president. Our relentless curiosity, interprofessional collaboration, leading-edge facilities, and purposeful inclusion of diverse perspectives and experiences give us an incredible advantage we can use to improve the health and well-being of people across the state of Arizona and around the world.

As we commemorate 55 years since the earliest days of the University of Arizona Health Sciences in 1967, we look forward to furthering our mission to educate the next generation of health care professionals, research and solve critical health care problems, and build healthier communities, Dr. Dake added.

On the education front, UArizona Health Sciences is developing new programs to address ongoing health care workforce shortages in three fields: physician assistant, doctor of physical therapy and certified nurse midwife.

UArizona Health Sciences also is preparing for the launch of two new research centers that will extend the reach of medicine into more precise treatments and another center that will use the knowledge gained from COVID-19 to better prepare for future pandemics.

The Center for Regenerative and Restorative Medicine will focus on developing cell-based technologies that diagnose disease or heal injured tissue.

The Center for Advanced Molecular and Immunological Therapies, to be based at the UArizona Health Sciences campus in Phoenix, will accelerate progress in the late-stage development and commercialization of personalized cell- and gene-based therapies for cancer, autoimmune disease, infectious disease and immune monitoring.

The Aegis Consortium will build partnerships with universities, foundations, nonprofits, governments and industries around the world to address gaps in pandemic preparedness ranging from virology and immunology to communications and policy, behavior, and the built and natural environments.

Three additional UArizona Health Sciences initiatives based in existing colleges and centers are specifically focused on improving health and wellness in Arizona.

The Telehealth Expansion initiative will increase health care access to rural and other underserved communitiesand provide additional telehealth training opportunities for current and future health care providers.

The Valley Fever Collaborative will connect the states three public universities to develop precision medicine approaches to treatment, expand drug and vaccine development, and pursue environmental risk abatement to reduce the financial cost and human burden of Valley fever.

The Arizona Melanoma and Skin Cancer Database initiative will build the only state registry and database of melanoma and non-melanoma skin cancer to better assess and address the full impact of the diseases.

Progress of UArizona Health Sciences new and existing education, research and outreach initiatives can be tracked on its Tomorrow is here website.

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UArizona Health Sciences to Expand Education, Research and Workforce Development in 2022 | UArizona Health Sciences - The University of Arizona Health...

University of Pennsylvania professor James Wilson signed a five-year renewable deal on behalf of his gene therapy laboratory to license its manufacturing process to the Center for Breakthrough Medicines, based in King of Prussia.

The center, in turn, has the exclusive right to make the Penn gene therapy labs manufacturing and analytics process available to other biotechnology and drug companies.

Under the agreement, Wilsons laboratory at Penn will receive $5 million in research funding a year with an option to renew for up to 15 years, for a potential investment of $75 million from the Center for Breakthrough Medicines, a contract development manufacturer specializing in cell and gene therapies. The center serves other firms on a contract basis to provide services from drug development to manufacturing, enabling companies to focus on drug discovery and marketing.

A shortage of expensive-to-build biotechnology laboratory and manufacturing space has prompted high demand for such facilities.

J. Brian ONeill, who founded Recovery Centers of America, a chain of alcohol and substance abuse rehabilitation centers, has been promoting his King of Prussia development project called Discovery Labs and the center, which he also owns as an answer.

He is outfitting space that could grow to roughly 700,000 square feet over time, said Audrey Greenberg, ONeills co-founder of the center.

Currently, the space including offices and warehouse occupies 200,000 square feet, with the next 300,000 coming online later this year or early 2023. Wilsons gene therapy operation currently operates in about half of the planned 150,000 square feet, with the other half expected to open later this year. Other tenants include British drugmaker GSK and WuXi Biologics, a Chinese-based contract development manufacturing organization.

High-tech space that fosters research and manufacturing may mean faster approval from regulators, allowing small biotech firms, universities, and large drug firms to advance from discovery to human studies with less risk and expense. This partnership gives our clients the potential to advance to investigational drug with a high-quality process, materials and analytical methods, Greenberg said.

Demand for labs from biotech start-ups and gene therapy companies, in particular, is booming in the region. Spark Therapeutics is slated to build a $575 million facility on Drexels campus, and other labs are expected in the former Budd Co. plant in North Philadelphia and former Hahnemann hospital facilities.

Landlords are also scrambling to retrofit existing office space to accommodate life-science labs. Brandywine, for example, is turning a 50,000-square foot section of the Cira Centre tower near 30th Street Station into lab and research space, while Keystone Property Group has transformed sections of its Curtis building across from Washington Square into life-science labs and offices for such tenants as brain cancer vaccine developer Imvax Inc. and Vivodyne.

In 2020, ONeill announced he was building the labs facility at a cost of $1.1 billion. Health-care private equity firm Deerfield Management of New York City was also an investor.

ONeills property is part of a planned network of lab and office buildings occupied by life-science tenants. The other components of Discovery Labs consist of The Inquirers former Schuylkill Printing Plant and office-park buildings that ONeills business bought from Liberty Property Trust.

Wilson heads Penn Medicines gene therapy program and his lab helped develop three cell and gene therapy compounds (Glybera, Luxturna, and Zolgensma). Wilson has also helped develop several viral vectors, inactivated viruses that deliver replacement genes into the body, that he has licensed to companies.

Earlier this month, the Center for Breakthrough Medicines received an infusion of $350 million from SK Inc., a publicly traded South Korean conglomerate that specializes in semiconductors, energy and now health care. Some of that $350 million will go toward funding the Penn partnership, Greenberg said.

Building gene therapy and other biotech drug production space is very capital intensive. Its expensive to build, costing up to $1,000 to $2,000 per square foot, when you factor in bioreactors and clean rooms, HVAC requirements and expertise, Greenberg said. A lot of money is going to hiring and training employees.

The center employs 150 people and hopes to expand to 600 employees by year end.

In addition, the space will allow other start-up companies a place to outsource drug research and production.

Our collaboration with ... Penn will allow the ability to offer accelerated gene therapy manufacturing services under one roof regardless of where a program is in its development timeline, Joerg Ahlgrimm, president and CEO of the center, said in a statement.

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Penn Medicine gene therapy lab inks deal with Center for Breakthrough Medicines in KOP - The Philadelphia Inquirer

Vaccine-like mRNA Injection Can Be Used to Make CAR T Cells in the Body

Experimental immunotherapy can temporarily reprogram patients immune cells to attack a specific target via only a single injection of messenger RNA (mRNA), similar to the mRNA-based COVID-19 vaccines, according to a new study from researchers in the Perelman School of Medicine at the University of Pennsylvania.

The researchers, whose work was published on January 6 in Science, demonstrated the new approach with an mRNA preparation that reprograms T cellsa powerful type of immune cellto attack heart fibroblast cells. Heart failure is often driven in part by these fibroblast cells, which respond to heart injury and inflammation by chronically overproducing fibrous material that stiffens the heart muscle, impairing heart functiona condition called fibrosis. In experiments in mice that model heart failure, the reduction in cardiac fibroblasts caused by the reprogrammed T cells led to a dramatic reversal of fibrosis.

Fibrosis underlies many serious disorders, including heart failure, liver disease, and kidney failure, and this technology could turn out to be a scalable and affordable way to address an enormous medical burden, said senior author Jonathan A. Epstein, chief scientific officer at Penn Medicine and executive vice dean and the William Wikoff Smith Professor of Cardiovascular Research in the Perelman School of Medicine. But the most notable advancement is the ability to engineer T cells for a specific clinical application without having to take them out of the patients body.

The new technique is based on chimeric antigen receptor (CAR) T cell technology, which, until now, has required the harvesting of a patients T cells and their genetic reprogramming in the lab to recognize markers on specific cell types in the body. These specially targeted T cells can then be multiplied using cell culture techniques and re-infused into the patient to attack a specific cell type. The first CAR T cell therapy was developed by researchers from Penn and Childrens Hospital of Philadelphia and approved by the U.S. Food and Drug Administration in 2017 for use against certain leukemias and later approved for lymphoma that arise from immune cells called B cells.

Although CAR T cell technology is currently used primarily for treating cancers, with dramatic results in many otherwise hopeless cases, its developers have long envisioned harnessing the approach for other diseases. Indeed, Dr. Epstein and colleagues showed in a 2019 study that the standard CAR T cell approach can be used to attack overactive cardiac fibroblasts and restore heart function in a mouse model of heart failure.

However, this standard CAR T cell strategy would be problematic when directed against heart failure or other fibrotic diseases in humans. Fibroblasts have a normal and important function in the body, especially in wound healing. CAR T cells that are reprogrammed genetically to attack fibroblasts could survive in the body for months or even years, suppressing the fibroblast population and impairing wound healing for all that time.

Therefore, in the new study, Dr. Epstein and colleagues devised a technique for a more temporary and controllable, and procedurally much simpler, type of CAR T cell therapy. They designed mRNA that encodes a T-cell receptor targeting activated fibroblasts and encapsulated the mRNA within tiny, bubble-like lipid nanoparticles (LNPs) that are themselves covered in molecules that home in on T cells. That technology is also crucial to the mRNA COVID-19 vaccines now in use across the globe.

Standard CAR T cell technology involves modifying patients T cells outside the body, which is expensive and difficult to scale for common diseases or for use in less wealthy countries, said study co-author Drew Weissman, the Roberts Family Professor in Vaccine Research at Penn. Making functional CAR T cells inside the body greatly extends the promise of the mRNA/LNP platform.

Injected into mice, the encapsulated mRNA molecules are taken up by T cells and act as templates for the production of the fibroblast-targeting receptor, effectively reprogramming the T cells to attack activated fibroblasts. This reprogramming is very temporary, however. The mRNAs are not integrated into T-cell DNA and survive within T cells for only a few daysafter which the T cells revert to normal and no longer target fibroblasts.

The scientists found that, despite this brief duration of activity, injections of the mRNA in mice that model heart failure successfully reprogrammed a large population of mouse T cells, causing a major reduction of heart fibrosis in the animals and a restoration of mostly normal heart size and function with no evidence of continued anti-fibroblast T cell activity one week after treatment.

The researchers are continuing to test this mRNA-based, transient CAR T cell technology, with the hope of eventually starting clinical trials.

Along with Drs. Epstein and Weissman, the other co-corresponding authors are Haig Aghajanian, co-founder and vice president of research at Capstan Therapeutics; and Hamideh Parhiz, a research assistant professor of medicine at Penn. Joel Rurik, the lead author, is a PhD candidate in Dr. Epsteins laboratory.

Funding for the study was provided by the National Institutes of Health.

Adapted from a Penn Medicine News article, January 6, 2022.

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Vaccine-like mRNA Injection Can Be Used to Make CAR T Cells in the Body - UPENN Almanac

PRESS RELEASE

AB SCIENCE HAS BEEN GRANTED AUTHORIZATION TO INITIATE PHASE II STUDY IN PATIENTS WITH SEVERE MAST CELL ACTIVATION SYNDROME BY THE FRENCH HEALTH AUTHORITY (ANSM)

Paris, 19 January, 2022, 6pm CET

AB Science SA (Euronext - FR0010557264 - AB) today announces that it has been authorized by the French Medicine Agency, ANSM, to initiate a Phase II study (AB20006) in patients with severe mast cell activation syndrome.

Study AB20006 is titled A 24-week, multicenter, randomized, double blind, placebo-controlled, dose-range finding phase 2 study to compare efficacy and safety of oral masitinib to placebo in treatment of patients with severe mast cell activation syndrome (MCAS) or severe smoldering or indolent systemic mastocytosis (SSM/ISM) with handicap unresponsive to optimal symptomatic treatment. The study will enroll 60 patients from numerous study centers. The treatment objective in severe MCAS is to reduce symptoms (pruritus, flush, depression) and improve impaired quality-of-life.

Study AB20006 has also been approved by the U.S. Food and Drug Administration (FDA).

Professor Olivier Hermine, President of the Scientific Committee of AB Science and member of the Acadmie des Sciences in France said, We are pleased to receive this ANSM approval to begin masitinib MCAS clinical trials in Europe, which when taken together with the previous FDA approval is a strong signal that masitinib has international KOL support in this indication. MCAS is a newly recognized disorder, distinct from but closely related to systemic mastocytosis and for which there is a far greater prevalence in the general population. Masitinibs proven ability to substantially reduced severe mast cell mediator release symptoms in mastocytosis, regardless of the patient's c-Kit mutational status [1,2], suggests that masitinib is particularly well-suited for the treatment of severe MCAS, for which there are currently no registered therapeutic drugs.

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MCAS is a disease caused by inappropriate activation of mast cells, which can lead to mast cell mediator release symptoms with a severity ranging from mild to life-threatening. In this aspect, MCAS is similar to indolent and smoldering systemic mastocytosis (ISM/SSM), however, important differences exist that make MCAS a distinct entity from systemic mastocytosis. In mastocytosis, well-defined mutations result in an aberrant population of mast cells with a marked increased proliferation in tissues, whereas MCAS is driven by greater (ill-defined) mutational heterogeneity that is associated with aberrant mast cell activation but only modest increases in mast cell numbers due to reduced apoptosis [3]. Another striking difference between systemic mastocytosis and MCAS is the prevalence of these diseases. Systemic mastocytosis is considered to be a rare, orphan disease affecting about 1/100,000 people, whereas MCAS has an estimated prevalence of 117% of the population (i.e., at least a 1000-fold difference) [4,5].

Because masitinib has been designed to be a potent inhibitor of mast cell activation (through its action against wild-type c-Kit, Lyn and Fyn tyrosine kinases), it is uniquely well-suited for the treatment of severe MCAS, unlike other c-Kit tyrosine kinase inhibitors that typically target specific c-Kit mutations that are associated with systemic mastocytosis. There are currently no approved therapies for severe MCAS or drugs in clinical development for this indication.

Reference[1] Lortholary O, Chandesris MO, Bulai Livideanu C, et al. Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study. Lancet. 2017;389(10069):612-620.

[2] Paul C, Sans B, Suarez F, et al. Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study. Am J Hematol. 2010;85:92125.

[3] Afrin LB, Ackerley MB, Bluestein LS, et al. Diagnosis of mast cell activation syndrome: a global "consensus-2". Diagnosis (Berl). 2020;8(2):137-152. Published 2020 Apr 22.

[4] Molderings GJ, Haenisch B, Bogdanow M, Fimmers R, Nthen MM. Familial Occurrence of Systemic Mast Cell Activation Disease. PLoS One. 2013;8:e76241.

[5] Haenisch B, Nthen MM, Molderings GJ. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunol. 2012; 137:197205.

About AB ScienceFounded in 2001, AB Science is a pharmaceutical company specializing in the research, development and commercialization of protein kinase inhibitors (PKIs), a class of targeted proteins whose action are key in signaling pathways within cells. Our programs target only diseases with high unmet medical needs, often lethal with short term survival or rare or refractory to previous line of treatment. AB Science has developed a proprietary portfolio of molecules and the Companys lead compound, masitinib, has already been registered for veterinary medicine and is developed in human medicine in oncology, neurological diseases, inflammatory diseases and viral diseases. The company is headquartered in Paris, France, and listed on Euronext Paris (ticker: AB).

Further information is available on AB Sciences website: http://www.ab-science.com.

Forward-looking Statements - AB ScienceThis press release contains forward-looking statements. These statements are not historical facts. These statements include projections and estimates as well as the assumptions on which they are based, statements based on projects, objectives, intentions and expectations regarding financial results, events, operations, future services, product development and their potential or future performance.

These forward-looking statements can often be identified by the words "expect", "anticipate", "believe", "intend", "estimate" or "plan" as well as other similar terms. While AB Science believes these forward-looking statements are reasonable, investors are cautioned that these forward-looking statements are subject to numerous risks and uncertainties that are difficult to predict and generally beyond the control of AB Science and which may imply that results and actual events significantly differ from those expressed, induced or anticipated in the forward-looking information and statements. These risks and uncertainties include the uncertainties related to product development of the Company which may not be successful or to the marketing authorizations granted by competent authorities or, more generally, any factors that may affect marketing capacity of the products developed by AB Science, as well as those developed or identified in the public documents published by AB Science. AB Science disclaims any obligation or undertaking to update the forward-looking information and statements, subject to the applicable regulations, in particular articles 223-1 et seq. of the AMF General Regulations.

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INFLAMMATION PROTEIN CONTRIBUTES TO ANEMIA OF CHRONIC DISEASE BY PREVENTING RED BLOOD CELL FORMATION

More than one billion people worldwide suffer from anemia of inflammation or anemia of chronic diseases (ACD) and for the first time we may know why. New research from The Feinstein Institutes for Medical Research, published in Blood, shows that high mobility group box-1 protein (HMGB1) prevents the bodys ability to produce sufficient levels of oxygen-rich red blood cells. The discovery opens up new avenues of research to develop therapies to target HMGB1 and better treat ACD.

For those with ACD, inflammation prevents the body from using stored iron to make enough healthy red blood cells, leading to anemia. Patients at risk for ACD include those with sepsis, autoimmune diseases, cancer and chronic kidney disease, among other conditions. Common hormone therapy to promote blood cell formation erythropoietin (EPO) treatment has been shown ineffective for those with ACD. The new study led by Lionel Blanc, PhD, suggests that HMGB1, a protein that signals inflammation in the body, interferes with EPO signaling to produce the needed blood cells.

You need red blood cells to carry oxygen throughout the body; the inability to do so is known as anemia. Patients with chronic inflammation often develop anemia, but the molecular understanding remains unclear, said Dr. Blanc, corresponding author of the study. Our findings pinpoint HMGB1 as potential cause for interrupting that critical hemoglobin formation and opens up new avenues of research to develop therapies to help those with ACD.

Dr. Blanc and his team had previously linked HMGB1 in sepsis-associated anemia in mice. HMGB1 is a protein that helps facilitate inflammation. In this study, researchers found that HMGB1 stops erythropoiesis by inhibiting the EPO signaling pathway in an in vitro (test tube) model of human erythropoiesis and in mice with chronic inflammation. This new knowledge helps add to the basic understanding of anemia of inflammation, resistance to EPO therapy and for future experimental therapeutic strategies to target HMGB1.

Dr. Blancs discovery solves a mystery that has puzzled physicians for decades, which is why does treatment with EPO fail to reverse the anemia of chronic disease, said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes and co-senior author on the paper. By unraveling a completely unsuspected mechanism attributable to HMGB1, these landmark results reveal a new direction in developing therapies for millions of patients in need.

Dr. Blanc is a recognized leader in hematology research. Most recently, he was selected as editor-in-chief of the journal Blood Cells, Molecules and Diseases which focuses on sharing peer-reviewed research around the study of hematology, cell biology, immunology, and human genetics.

About the Feinstein Institutes

The Feinstein Institutes for Medical Research is the home of the research institutes of Northwell Health, the largest health care provider and private employer in New York State. Encompassing 50 research labs, 3,000 clinical research studies and 5,000 researchers and staff, the Feinstein Institutes raises the standard of medical innovation through its five institutes of behavioral science, bioelectronic medicine, cancer, health system science, and molecular medicine. We make breakthroughs in genetics, oncology, brain research, mental health, autoimmunity, and are the global scientific leader in bioelectronic medicine a new field of science that has the potential to revolutionize medicine. For more information about how we produce knowledge to cure disease, visit http://feinstein.northwell.edu and follow us on LinkedIn.

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CORRECTING and REPLACING CAPTION Inflammation Protein Contributes to Anemia of Chronic Disease by Preventing Red Blood Cell Formation - Business Wire

CYNK-101 is an investigational genetically modified natural killer (NK) cell therapy designed to synergize with antibody therapeutics for difficult to treat cancers of high unmet medical need

Phase 1/2a clinical trial will evaluate the safety and preliminary efficacy of CYNK-101 in combination with standard chemotherapy, trastuzumab and pembrolizumab in first-line advanced HER2/neu positive gastric and gastroesophageal junction cancer

Third fast track designation received by Celularity within twelve months from the U.S. FDA following fast track designations for CYNK-001, an unmodified NK cell therapy in development for the treatment of acute myeloid leukemia and CYNK-001 in development for the treatment of recurrent glioblastoma multiforme

FLORHAM PARK, N.J., Jan. 18, 2022 (GLOBE NEWSWIRE) -- Celularity Inc. (Nasdaq: CELU) (Celularity), a clinical-stage biotechnology company developing placental-derived off-the-shelf allogeneic cell therapies, today announced the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation for its genetically modified cryopreserved human placental hematopoietic stem cell-derived natural killer (NK) cell therapy, CYNK-101, which is being developed in combination with standard chemotherapy, trastuzumab and pembrolizumab in patients in first-line locally advanced unresectable or metastatic HER2/neu positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. CYNK-101 is an investigational genetically modified NK cell therapy designed to synergize with approved antibody therapeutics through enhanced antibody-dependent cellular cytotoxicity (ADCC).

Robert Hariri, M.D., Ph.D., Founder, Chairperson and Chief Executive Officer of Celularity, said, We are extremely excited to receive this fast track designation and the support from the FDA for our investigational genetically modified NK cell therapy in the first-line setting of G/GEJ cancers. CYNK-101 is built on the foundation of our unique placental-derived source material, which as compared to other cell sources, has naturally enhanced proliferative potential (or stemness), that has been shown to be a determinant of persistence and efficacy potential. Using novel genetic engineering, we have enhanced the ability of CYNK-101 cells to synergize with approved antibodies and provide a novel and potentially non-cross resistant therapy to improve the lives of patients with G/GEJ cancers as well as a broad range of other indications.

The addition of immune-based therapy of blocking PD-1 with a checkpoint inhibitor (pembrolizumab) to the prior standard of care (chemotherapy and traztuzumab) has recently been shown to be of benefit in patients with first-line HER2/neu positive unresectable G/GEJ cancer, added Andrew Pecora, M.D., President of Celularity. While overall response rates in first-line G/GEJ treated with the triple combination of chemotherapy, traztuzumab and pembrolizumab were significantly greater with the addition of pembrolizumab (74.4% vs 51.9%; p=0.000006; Keynote-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer; Janjigian Y et al., Nature 600, 727-730 (2021), complete response rates remained modest, however (11.3%). Our recently accepted IND enables the assessment to possibly further improve outcomes in G/GEJ treated with triple combination therapy by adding CYNK-101 cells, a potentially non-cross resistant therapy (enhanced ADCC, direct NK cell tumor killing and help of T cell function and memory) after initially cytoreducing the tumor mass and potentially diminishing resistance in the tumor microenvironment with combined chemotherapy, traztuzumab and pembrolizumab induction followed by reinduction and maintenance with CYNK-101 cells in combination with traztuzumab and pembrolizumab.

About Fast Track Designation

Fast Track Designation is an FDA process designed to facilitate the development and expedite the review of new drugs that are intended to treat a serious condition and have the potential to address unmet medical needs. The purpose of Fast Track designation is to expedite the process of getting important new drugs to patients. The designation may offer frequent interactions with the FDA review team on the products development and the product may be eligible for rolling review and priority review if certain criteria are met.

About Gastric Cancer

Gastric cancer is the fifth most common cancer worldwide(1). Despite recent improvements in treatment quality and options, advanced gastric cancer remains one of the hardest to cure cancers, with a median overall survival (OS) of 1012 months and a five-year OS of approximately 520%. In May 2021, the U.S. FDA granted accelerated approval to pembrolizumab in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2+ G/GEJ cancers (2)

REFERENCES

About CYNK-101

Celularitys lead therapeutic candidate based on its placental-derived genetically modified NK cell type is CYNK-101, an allogeneic, off-the-shelf human placental CD34+-derived NK cell product genetically modified to express high-affinity and cleavage-resistant CD16 (FCGRIIIA) variant to drive antibody-dependent cell-mediated cytotoxicity. Currently CYNK-101 is being developed as a treatment in combination with standard chemotherapy, trastuzumab and pembrolizumab for HER2+ overexpressing gastric or gastroesophageal junction adenocarcinoma. The safety and efficacy of CYNK-101 have not been established, and CYNK-101 has not been approved for any use by the U.S. Food and Drug Administration or any other analogous regulatory authority.

About Celularity

Celularity Inc. (Nasdaq: CELU) headquartered in Florham Park, N.J., is a clinical stage biotechnology company leading the next evolution in cellular medicine by developing allogeneic cryopreserved off-the-shelf placental-derived cell therapies, including therapeutic programs using unmodified natural killer (NK) cells, genetically modified NK cells, T-cells engineered with a CAR (CAR T-cells), and mesenchymal-like adherent stromal cells (ASCs). These therapeutic programs target indications in cancer, infectious and degenerative diseases. In addition, Celularity develops and manufactures innovative biomaterials also derived from the postpartum placenta. Celularity believes that by harnessing the placentas unique biology and ready availability, it can develop therapeutic solutions that address significant unmet global needs for effective, accessible, and affordable therapies.

To learn more, visit celularity.com.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995, as well as within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical facts are forward-looking statements, including those relating to future events. In some cases, you can identify forward-looking statements by terminology such as anticipate, believe, can, contemplate, continue, could, estimate, expect, forecast, intends, may, might, outlook, plan, possible, potential, predict, project, seek, should, strive, target, will, would and the negative of terms like these or other comparable terminology, and other words or terms of similar meaning. The forward-looking statements in this press release include, statements regarding the Phase 1/2a clinical trial of CYNK-101, CYNK-101s ability to improve clinical outcomes, CYNK-101s ability to complement and synergize with a range of antibody treatment strategies, and the ability to combine the advantages of placental-derived cellular therapies with approved treatment strategies, among others. Many factors could cause actual results to differ materially from those described in these forward-looking statements, including but not limited to: the risk that CYNK-101 does not complement and synergize with a range of antibody treatment strategies, the risk that CYNK-101 will have limited success targeting HER2 in combination with chemotherapy, the risk that preclinical studies may not have the same results in clinical trials, along with the inherent risks in biotechnological development, including with respect to the development of novel cellular therapies, and the clinical trial and regulatory approval process; and risks associated with developments relating to Celularitys competitors and industry, along with those risk factors set forth under the caption Risk Factors in Celularitys prospectus filed with the Securities and Exchange Commission (SEC) on August 12, 2021 and other filings with the SEC. These risks and uncertainties may be amplified by the ongoing COVID- 19 pandemic. If any of these risks materialize or underlying assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. There may be additional risks that Celularity does not presently know, or that Celularity currently believes are immaterial, that could also cause actual results to differ from those contained in the forward-looking statements. In addition, these forward-looking statements reflect Celularitys current expectations, plans, or forecasts of future events and views as of the date of this communication. Subsequent events and developments could cause assessments to change. Accordingly, forward-looking statements should not be relied upon as representing Celularitys views as of any subsequent date, and Celularity undertakes no obligation to update forward-looking statements to reflect events or circumstances after the date hereof, whether as a result of new information, future events or otherwise, except as may be required under applicable securities laws.

Celularity Investor Contacts:Carlos Ramirez SVP, Investor RelationsCelularity Inc.carlos.ramirez@celularity.com

Celularity Media ContactJason Braco, Ph.D.LifeSci Communicationsjbraco@lifescicomms.com

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Celularity Receives Fast Track Designation from US FDA for its NK Cell Therapy CYNK-101 in Development for the First-Line Treatment of Advanced...

Two scientists who are pioneering innovators of the imaging technology known as enhanced Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) will be coming to Yale School of Medicine. C. Shan Xu, PhD, will join the faculty in the Department of Cellular and Molecular Physiology and Song Pang, MS, will lead collaborations using this technology via a FIB-SEM Collaboration Core. The arrival of these two outstanding scientists will allow us to build upon Yales strengths in imaging and advance as a leader in cutting-edge imaging technology, says Nancy J. Brown, MD, Jean and David W. Wallace Dean of Medicine. Their expertise will have a major impact on basic science discoveries that will deepen our understanding of human biology.

Almost 500 years ago Andreas Vesalius published De Humani Corporis Fabrica Libri Septem, a revolutionary anatomy text that was the first to contain illustrations of the human body based on observations from dissections. Vesalius instinctively knew that the human body could only be understood by developing a three-dimensional appreciation of how its tissues and organs fit together. While he was limited to what could be perceived by the human eye, today, sophisticated microscopy allows us to view the three-dimensional structure of tissues and organs at the cellular and subcellular level. This is fundamental to achieving scientific breakthroughs that drive medical advances. In 2018, Yale acquired the only focused ion beam-scanning electron microscope in the region. FIB-SEM opens up the possibility of examining cellular structuresand how they relate to one anotherin three dimensions. FIB-SEM is a beautiful tool that helps us connect form to function, says Michael Caplan, PhD 87, MD 87, chair and C.N.H. Long Professor of Cellular and Molecular Physiology.

But the technology has limitations. It works as a kind of micro-machining tool that uses high-energy gallium ions to etch away ultra-thin layers of tissue that have been embedded in plastic, generating a series of images that must be painstakingly aligned and combined to create the final image. Its a slow process in which only small volumes of tissue can be imaged over a period of several days. To image larger volumes would require operating for much longer periods of time, during which the process is inevitably interrupted due to ion source replenishment and system glitches that lead to defects in the final image.

At the Janelia Research Campus of Howard Hughes Medical Institute, where Xu currently directs FIB-SEM Technologies and Pang is a research application scientist in the FIB-SEM Technology Division, Xu is the lead inventor of enhanced FIB-SEM. This technology expands the imageable volume by orders of magnitude, achieves 3D isotropic resolutions of eight and four nanometersabout one 25,000th of the width of a hairand improves its stability to reach 100% effective reliability. These advances enable the platform to continuously run for months or years instead of days and to generate images that, when assembled, are free of defects.

Enhanced FIB-SEM has enabled discoveries in tissue biology, cell biology, and the connectomethe system of neural pathways in the brain. Recently, it enabled an open-access high-resolution 3D atlas of whole cells and tissues, from cancer and immune cells to mouse pancreatic islets and Drosophila neural tissues. It was also used to image the circuitry of a large portion of the Drosophila brain, the largest and most detailed connectome to date. With 25,000 neurons and 4,00 cell types, it took two years and two microscopes to complete. The technology has continued to advance and allowed for the image acquisition of the entire Drosophila central nervous system, consisting of approximately 200,000 neurons, a yearlong process involving eight FIB-SEMs running in parallel.

Enhanced FIB-SEM will build upon and complement YSMs existing strength in FIB-SEM, which was established within the Center for Cellular and Molecular Imaging (CCMI) Electron Microscopy Facility by its director, Xinran Liu, MD, PhD, who expertly oversees its operation. Yale investigators will have the opportunity to apply these technologies to an extraordinarily diverse palette of tissues and scientific questions. Pang and Xu are already collaborating with Yale researchers to explore structures that had never before been studied with such powerful imaging technology.

With 29 years of experience in technology invention and application development, Xu holds 22 patents and is actively involved in teaching courses and leading workshops on volume electron microscopy worldwide. At Yale School of Medicine, he plans to develop the next generation of FIB-SEM technology, aiming to further advance the 3D isotropic resolution and use cryogenic techniques to image cells in their native state (by cooling them to very low temperatures instead of fixing them in plastic) but at much larger volumes. Xu will also work to develop FIB-SEM into a tool that can report on much more than a specimens physical appearance. Electron microscopy generates black and white images that illustrate the structure of a specimen but provide little information on its chemical composition. By redesigning the ways in which the images are collected, he hopes to unlock a previously inaccessible trove of biochemical detail.

These improvements will allow scientists to better study the structure and relationships of molecules within the cellular environment. Scientists now understand that organelles within cells are in physical contact and communicate with one another, which affects the regulation of their function. Enhanced FIB-SEM allows us to see those contacts and how they change as a result of different physiological stimuli, says Caplan. It will allow us to understand not only at a structural level how cells are organized, but also how that organization is shaped by and responds to stimuli.

The arrival of Xu and Pang continues not only the legacy of Vesalius, but also Yale School of Medicines tradition of using imaging as a powerful tool for discovery. In the 1950s, George Paladea Nobel laureate who is widely considered the father of modern cell biology and was the founding chair of the Department of Cell Biologyrecognized the power of electron microscopy. It wasnt lost on Xu or Caplan, for whom Palade served as a thesis advisor, that Palade would have been awed by the images generated by enhanced FIB-SEM. Palade subscribed to the notion that form follows function, making Physiology, which connects the properties of molecules to the properties of higher order biological structures, the logical home for Xu and Pang.

Xu and Pang are eager to bring enhanced FIB-SEM to Yale for the opportunity to work with human tissue to create a connection between basic science and clinical models and develop robust datasets that researchers can mine. We can combine this cutting-edge state-of-the-art technology with Yales world class scientists who can utilize it to enable their amazing discoveries, said Xu. Added Pang, What we really want to do is to cultivate a rich ecosystem from the image to data analysis to discovery.

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Newly Recruited Scientists Bring Innovative Imaging Technology to YSM - Yale School of Medicine

Researchers at the Wayne State University School of Medicine and the National Institutes of Healths Perinatology Research Branch in Detroit have found that SARS-CoV-2, the virus that causes COVID-19, may cause fetal inflammation even in the absence of placental infection.

Pregnant women have a higher risk of severe illness if infected with COVID-19. Infection increases the risk of preterm birth, stillbirth and preeclampsia.

Maternal-fetal immune responses in pregnant women infected with SARS-CoV-2, published today in the journal Nature Communications, reports that COVID-19 infection during pregnancy may cause inflammatory immune responses in the fetus, even if the virus does not infect the placenta.

The study, conducted by Nardhy Gomez-Lopez, Ph.D., associate professor of the WSU Department of Obstetrics and Gynecology, and section head of the Maternal-Fetal Immunobiology Unit, and Roberto Romero, M.D., D.Med.Sci., chief of the NIHs Perinatology Research Branch, based at the Wayne State University School of Medicine, and professor of Molecular Obstetrics and Genetics at the WSU School of Medicine, details changes in antibodies, immune cell types and inflammatory markers in maternal blood, umbilical cord blood and placental tissues.

We found that in pregnant mothers who contract the virus, SARS-CoV-2 induces a fetal immune response even in the absence of placental infection or symptoms in the newborn. The potential long-term effects of this inflammatory process on infants requires further study, Dr. Gomez-Lopez said.

The researchers evaluated 23 pregnant women. Twelve tested positive for SARS-CoV-2, and of those, eight were asymptomatic, one had mild symptoms and three had severe COVID-19. After delivery, the researchers compared immune responses between mothers and their newborns by comparing maternal blood and umbilical cord blood. Inflammatory immune responses triggered by the virus were observed in women, their newborns and placental tissues regardless of whether the mothers displayed symptoms.

The study team described the following observations:

Pregnant women with SARS-CoV-2 had a reduction in an immune cell type called T-cells, which helps drive antiviral responses.

Infected mothers developed antibodies against the virus whether or not they had symptoms, and some of these antibodies were found in the umbilical cord blood.

Infected mothers had a higher level of immune activity markers (i.e., cytokines) in blood regardless of symptoms. The elevated cytokines are interleukin-8, interleukin-15 and interleukin-10.

Infants born to infected mothers, even if the mother had no symptoms, had an inflammatory response reflected by higher levels of interleukin-8. This elevation was observed even though the fetus presumably did not have COVID-19.

While the virus was absent in placentas, the placentas from infected mothers had altered ratios of immune cell types. The researchers also found altered immune activity (measured by changes in RNA transcripts) in the placenta and cord blood of infants born to infected mothers. These findings indicate that the neonatal immune system is affected by maternal infection by SARS-CoV-2 even if the virus is not detected in the placenta.

This study provides insight into the maternal-fetal immune responses triggered by SARSCoV-2 and emphasizes the rarity of placental infection, Dr. Romero said. Most pregnant women withSARS-CoV-2 infection are asymptomatic or only experience mild symptoms. Regardless, in the first six months of the COVID-19 pandemic, it was documented that infected pregnant women are at an increased risk for hospitalization, mechanical ventilation, intensive care unit admission and preterm birth, but rates of maternal mortality were reported to be similar between pregnant and non-pregnant women. More recently, it has been clearly shown that pregnant women are at high risk for severe disease and death, as well as preterm birth. Investigating host immune responses in pregnant women who are infected, even if they are asymptomatic, is timely.

These latest findings will help researchers better understand COVID-19 during pregnancy. The authors noted that the potential long-term effects of this inflammatory process on infants requires further study.

This research was supported by the Perinatology Research Branch, Division of Obstetrics and MaternalFetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services under Contract No. HHSN275201300006C. This research was also supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.

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COVID-19 may cause fetal inflammation even in absence of placental infection, researchers report - The South End

STRASBOURG, France & SUZHOU, China--(BUSINESS WIRE)--Regulatory News:

Transgene (Euronext Paris: TNG) (Paris:TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, and PersonGen BioTherapeutics, a Chinese biotech company at clinical trial stage, which is developing breakthrough and innovative CAR-T cell therapies for solid tumors and hematologic tumors, today announced a strategic collaboration to evaluate the feasibility and efficacy of combination therapy associating PersonGen's TAA06 CAR-T cell injection with intravenous (IV) administration of an armed oncolytic virus, from Transgenes Invir.IO platform, in solid tumors including pancreatic cancer and brain glioma. The collaboration aims to demonstrate the combinations likely synergistic mechanisms to potentiate CAR-T cell therapy.

Under the terms of the collaboration agreement, Transgene will develop multiple new OV candidates, using its patented oncolytic virus backbone VVcopTK-RR- and its Invir.IO technology platform, specifically for IV administration in combination with PersonGen's TAA06 CAR-T injection. PersonGen will evaluate the efficacy of the combination to eliminate solid tumors in preclinical models.

While CAR-T cell drugs have achieved great success in the treatment of hematological tumor therapies, there are many clinical challenges with the use of these novel therapies to treat solid tumors. One of the most critical obstacles is that the solid tumor microenvironment not only obstructs the homing of CAR-T cells, but also inhibits CAR-T cells' function. In addition, the high heterogeneity of solid tumors also facilitates immune escape from CAR-T cell therapy.

TAA06, has been independently developed by PersonGen, which has filed an investigational new drug (IND) application for this novel CAR-T therapy in China and will initiate the IND in the US later this year. Preclinical studies with TAA06, including pharmacodynamic data have shown superior in vivo and in vitro therapeutic efficacy in solid tumors.

Patented VVcopTK-RR- oncolytic viruses developed with Transgenes Invir.IO platform are able to:

Clinical and preclinical data has demonstrated that after IV administration, VVcopTK-RR- oncolytic viruses selectively replicate and persist in tumor cells leading to the local expression of its functional payload1.

Based on these highly supportive data, Transgene and PersonGen believe that combining Transgenes OV and PersonGens CAR-T therapies could overcome the challenges of solid tumor heterogeneity by improving the tumor microenvironment.

***

About TransgeneTransgene (Euronext: TNG) is a biotechnology company focused on designing and developing targeted immunotherapies for the treatment of cancer. Transgenes programs utilize viral vector technology with the goal of indirectly or directly killing cancer cells.The Companys clinical-stage programs consist of two therapeutic vaccines (TG4001 for the treatment of HPV-positive cancers, and TG4050, the first individualized therapeutic vaccine based on the myvac platform) as well as two oncolytic viruses (TG6002 for the treatment of solid tumors, and BT-001, the first oncolytic virus based on the Invir.IO platform).With Transgenes myvac platform, therapeutic vaccination enters the field of precision medicine with a novel immunotherapy that is fully tailored to each individual. The myvac approach allows the generation of a virus-based immunotherapy that encodes patient-specific mutations identified and selected by Artificial Intelligence capabilities provided by its partner NEC.With its proprietary platform Invir.IO, Transgene is building on its viral vector engineering expertise to design a new generation of multifunctional oncolytic viruses. Transgene has an ongoing Invir.IO collaboration with AstraZeneca.Additional information about Transgene is available at: http://www.transgene.fr.Follow us on Twitter: @TransgeneSA

About PersonGenPersonGens vision and goal are to develop high-quality cellular therapeutics that cancer patients really need. Founded in 2010, PersonGen has turned into a state-level high-tech enterprise focusing on R&D of breakthrough and innovative cellular immunotherapy technology and drug products for cancers. The company is dedicated to developing first-in-class and best-in-class CAR-T cell drugs. The Headquarter and the R&D Center (PersonGen -Suzhou is located in SIP, Suzhou, Jiangsu Province; the Industrial Cell Manufacturing Center (PersonGen-Anke) is located in Hefei, Anhui Province; and a newly formed Center for Cell Preparation and Supply is located in Shijiazhuang, Hebai Province, which aims to have northern part of China covered under its service supply-chain.Since its inception, the company has continuously gained the favor of investors. In 2012, PersonGen received angel round investment from Suzhou Industrial Park (SIP) Leading Venture Capital, Suzhou Industrial Park Venture Capital Guide Fund and other partners. In 2015 and 2016, it received strategic investment from Anhui Anke Biotechnology (Group) Co.,Ltd.. At the beginning of 2021, PersonGen (Suzhou) and PersonGen-Anke completed a major internal restructuring and followed by A round of investment of nearly 100 million yuan from YuanBio Venture Capital, Puenguoxin Equity Investment and Sangel Capital. At the end of 2021, the restructured PersonGen attracted B round financing of over 200 million yuan co-led by CCIC and Huatai Securities, and co-invested by Panyi Capital and Huatong Capital. This B round investment provides a greater impetus for the further development of PersonGen.With its first-class R&D capabilities on cell therapy drugs, its automatic CAR-T cell preparation pipeline, and advanced lentiviral vector industrial process system, PersonGen has successfully developed several first-in-class and best-in-class therapeutic cell products, covering most hematological tumors and some solid tumors. Among them, first-in-class PA3-17 injection for T-lymphoblastic leukemia/lymphoma is the first autologous CD7-CAR-T cell drug candidate in the world that was approved for registered clinical trials, and it was designated as an orphan drug by the US FDA; the TAA06 CAR-T cell injection, developed for treating solid tumors in children and adults, has demonstrated outstanding tumor clearance efficacy in preclinical studies, and is now entering into the IND application phase in China.For more information, please visit http://www.persongen.com.

Transgene disclaimerThis press release contains forward-looking statements, which are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those anticipated. The occurrence of any of these risks could have a significant negative outcome for the Companys activities, perspectives, financial situation, results, regulatory authorities agreement with development phases, and development. The Companys ability to commercialize its products depends on but is not limited to the following factors: positive pre-clinical data may not be predictive of human clinical results, the success of clinical studies, the ability to obtain financing and/or partnerships for product manufacturing, development and commercialization, and marketing approval by government regulatory authorities. For a discussion of risks and uncertainties which could cause the Companys actual results, financial condition, performance, or achievements to differ from those contained in the forward-looking statements, please refer to the Risk Factors (Facteurs de Risque) section of the Universal Registration Document, available on the AMF website (http://www.amf-france.org) or on Transgenes website (www.transgene.fr). Forward-looking statements speak only as of the date on which they are made, and Transgene undertakes no obligation to update these forward-looking statements, even if new information becomes available in the future.

1 Cassier et al. Bioavailability and activity of oncolytic virus TG6002 after intravenous administration in patients with advanced gastrointestinal carcinomas ESMO 2021, 1621 September 2021, Poster presentation;Bendjama et al. Oncolytic virus TG6002 locates to tumors after intravenous infusion and induces tumor-specific expression of a functional pro-drug activating enzyme in patients with advanced gastrointestinal carcinomas 2021 AACR Annual Meeting, April 9-14, 2021, Poster presentation

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Transgene and PersonGen Announce Collaboration to Evaluate a New Combination Therapy Against Solid Tumors - Business Wire