Category Archives: Cell Medicine

This article was written by Mo Ebrahimkhani, an associate professor of pathology and bioengineering at Pitt,for The Conversation. Faculty members and researchers who want to learn more about publishing in The Conversation canread about the process here.

Imagine if researchers could program stem cells, which have the potential to grow into all cell types in the body, so that they could generate an entire human organ. This would allow scientists to manufacture tissues for testing drugs and reduce the demand for transplant organs by having new ones grown directly from a patients cells.

Im a researcher working in this new fieldcalled synthetic biologyfocused on creating new biological parts and redesigning existing biological systems. In a new paper, my colleagues and I showed progress in one of the key challenges with lab-grown organsfiguring out the genes necessary to produce the variety of mature cells needed to construct a functioning liver.

Induced pluripotent stem cells, a subgroup of stem cells, are capable of producing cells that can build entire organs in the human body. But they can do this job only if they receive the right quantity of growth signals at the right time from their environment. If this happens, they eventually give rise to different cell types that can assemble and mature in the form of human organs and tissues.

The tissues researchers generate from pluripotent stem cells can provide a unique source for personalized medicine from transplantation to novel drug discovery.

But unfortunately, synthetic tissues from stem cells are not always suitable for transplant or drug testing because they contain unwanted cells from other tissues, or lack the tissue maturity and a complete network of blood vessels necessary for bringing oxygen and nutrients needed to nurture an organ. That is why having a framework to assess whether these lab-grown cells and tissues are doing their job, and how to make them more like human organs, is critical.

Inspired by this challenge, I was determined to establish a synthetic biology method to read and write, or program, tissue development. I am trying to do this using the genetic language of stem cells, similar to what is used by nature to form human organs.

I am a researcher specializing in synthetic biology and biological engineering at the Pittsburgh Liver Research Center and McGowan Institute for Regenerative Medicine, where the goals are to use engineering approaches to analyze and build novel biological systems and solve human health problems. My lab combines synthetic biology and regenerative medicine in a new field that strives to replace, regrow or repair diseased organs or tissues.

I chose to focus on growing new human livers because this organ is vital for controlling most levels of chemicalslike proteins or sugarin the blood. The liver also breaks down harmful chemicals and metabolizes many drugs in our body. But the liver tissue is also vulnerable and can be damaged and destroyed by many diseases, such as hepatitis or fatty liver disease. There is a shortage of donor organs, which limits liver transplantation.

To make synthetic organs and tissues, scientists need to be able to control stem cells so that they can form into different types of cells, such as liver cells and blood vessel cells. The goal is to mature these stem cells into miniorgans, or organoids, containing blood vessels and the correct adult cell types that would be found in a natural organ.

One way to orchestrate maturation of synthetic tissues is to determine the list of genes needed to induce a group of stem cells to grow, mature and evolve into a complete and functioning organ. To derive this list I worked with Patrick Cahan and Samira Kiani to first use computational analysis to identify genes involved in transforming a group of stem cells into a mature functioning liver. Then our team led by two of my studentsJeremy Velazquez and Ryan LeGrawused genetic engineering to alter specific genes we had identified and used them to help build and mature human liver tissues from stem cells.

The tissue is grown from a layer of genetically engineered stem cells in a petri dish. The function of genetic programs together with nutrients is to orchestrate formation of liver organoids over the course of 15 to 17 days.

I and my colleagues first compared the active genes in fetal liver organoids we had grown in the lab with those in adult human livers using a computational analysis to get a list of genes needed for driving fetal liver organoids to mature into adult organs.

We then used genetic engineering to tweak genesand the resulting proteinsthat the stem cells needed to mature further toward an adult liver. In the course of about 17 days we generated tinyseveral millimeters in widthbut more mature liver tissues with a range of cells typically found in livers in the third trimester of human pregnancies.

Like a mature human liver, these synthetic livers were able to store, synthesize and metabolize nutrients. Though our lab-grown livers were small, we are hopeful that we can scale them up in the future. While they share many similar features with adult livers, they arent perfect and our team still has work to do. For example, we still need to improve the capacity of the liver tissue to metabolize a variety of drugs. We also need to make it safer and more efficacious for eventual application in humans.

Our study demonstrates the ability of these lab livers to mature and develop a functional network of blood vessels in just two and a half weeks. We believe this approach can pave the path for the manufacture of other organs with vasculature via genetic programming.

The liver organoids provide several key features of an adult human liver such as production of key blood proteins and regulation of bilea chemical important for digestion of food.

When we implanted the lab-grown liver tissues into mice suffering from liver disease, it increased the life span. We named our organoids designer organoids, as they are generated via a genetic design.

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Genetic Engineering Transformed Stem Cells Into Working Mini-Livers That Extended the Life of Mice With Liver Disease - UPJ Athletics

CAMBRIDGE, Mass., Dec. 7, 2020 /PRNewswire/ --Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, today announced data from six oral and poster presentations highlighted at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition. These data demonstrate the company's broad efforts to understand the disease burden, accelerate the diagnosis and transform the treatment of systemic mastocytosis (SM).

"The medical needs in systemic mastocytosis are significant and urgent, and our presentations at the ASH annual meeting demonstrate our efforts to help address these challenges in collaboration with disease experts and the patient community," said Andy Boral, M.D., Ph.D., Chief Medical Officer at Blueprint Medicines. "AYVAKIT, an investigational precision therapy for the treatment of SM, is the only potent KIT D816V inhibitor to show a high complete remission rate in advanced SM, as well as improvements in mast cell burden, disease symptoms and quality of life in non-advanced SM. With this foundation of unprecedented clinical data, we continue to build momentum toward bringing AYVAKIT to patients. Later this month, we plan to submit a supplemental new drug application to the FDA for AYVAKIT for advanced SM, and we continue to globally enroll the registrational PIONEER trial for non-advanced SM."

Pure Pathologic Response (PPR) Measures Reduction and Elimination of Mast Cell Burden in Advanced SM, and Significantly Correlates with Improved Overall Survival (OS)

The IWG-MRT-ECNM response criteria (IWG criteria) are the current clinical and regulatory standard for evaluating treatment response in patients with advanced SM, and are primarily based on the resolution of organ damage. With the development of a potent and selective KIT D816V inhibitor, new PPR criteria were established by global SM experts in collaboration with Blueprint Medicines to measure objective reductions and elimination of neoplastic mast cells at the pathological and molecular level. These assessments are used in routine clinical practice, making the criteria more practical in the real-world setting.

In the Phase 1 EXPLORER trial, 53 patients with advanced SM were treated with AYVAKIT and evaluable for response per modified IWG criteria as of a data cutoff of May 27, 2020. The overall response rate (ORR) was 75 percent, and the rate of complete remission with full or partial hematologic recovery (CR/CRh) was 36 percent per modified IWG criteria, consistent with previously reported data. In the same population, the ORR was 77 percent and the CR/CRh rate was 47 percent per PPR criteria. Twenty-five percent of patients had a molecular CR/CRh, with no measurable evidence of residual KIT D816V mutation in the blood or bone marrow. Importantly, patients with a PPR response at six months had significantly improved OS (p=0.013). In the EXPLORER trial, AYVAKIT was generally well-tolerated, and safety data were consistent with previously reported results.

"For patients with advanced systemic mastocytosis, our primary treatment goals are to rapidly reduce their mast cell burden, improve quality of life, and importantly, prolong survival," said Jason Gotlib, M.D., M.S., Professor of Medicine, Hematology, at the Stanford Cancer Institute and an investigator on the EXPLORER trial. "To advance clinical research, it is important to establish objective measures of response that correlate with clinically significant outcomes and can be broadly incorporated into medical practice. The development of pure pathologic response criteria is a promising approach for assessing treatment response to avapritinib and its impact on survival, and clinically validates the role of KIT D816V inhibition in advanced mast cell disease."

Highly Sensitive Blood-Based Droplet Digital Polymerase Chain Reaction (ddPCR) Test Detects KIT D816V Mutation in 95% of Patients

Registry data have shown a median delay of nine years from symptom onset to diagnosis in patients with non-advanced SM,1 highlighting the need for new diagnostic tools.

In Part 1 of the PIONEER trial of AYVAKIT in patients with non-advanced SM, the sensitivity of ddPCR and next-generation sequencing (NGS) KIT D816V testing was evaluated. As of a data cutoff of December 27, 2019, in all 39 enrolled patients who received testing, a blood-based ddPCR test identified the KIT D816V mutation in 95 percent of patients, compared to 28 percent of patients evaluated by an NGS test performed on bone marrow aspirates. In addition, the ddPCR-based KIT D816V test was more sensitive compared to measurements of serum tryptase (77 percent) and bone marrow mast cells (90 percent) using standard World Health Organization diagnostic criteria. These results highlight the clinical value of blood-based, ddPCR-based KIT D816V testing as a confirmatory diagnostic tool to facilitate identification of patients with non-advanced SM, and a non-invasive screening tool for identifying patients with suspected advanced SM that requires a confirmatory bone marrow biopsy.

SM Patients Reported Worse Physical Functioning and Mental Health Compared to Historical Data for Patients with Lung and Colorectal Cancer

SM is characterized by unpredictable, severe and life-threatening complications despite best supportive care. To better understand the burden of disease, Blueprint Medicines is collaborating with clinical experts on the TouchStone survey, a study of adults with SM (n=56), and allergists/immunologists (n=60) and hematologists/oncologists (n=59) who care for patients with SM.

The TouchStone survey showed that SM symptoms have a profound impact on patients' daily functioning, mental health, and ability to work or perform usual activities. Compared to prior research on colorectal and lung cancer patients, participants reported worse physical functioning and mental health based on the 12-item Short Form Survey (SF-12) questionnaire, a valid and widely used health status measure. More than half of patients (54 percent) reported reduced hours at work, and 32 percent filed for medical disability due to their SM. Respondents cited the use of multiple over-the-counter and prescription medications, and frequent visits to physician specialists and the emergency department to manage their SM. In a one-year period, 30 percent of participants reported going to the emergency room at least once for anaphylaxis.

Healthcare providers broadly recognized the high disease burden in SM. A majority reported that non-advanced SM patients under their care feel depressed or discouraged, and limit their activities due to pain or discomfort. For healthcare providers, the most important treatment goals for advanced and non-advanced SM are improved progression-free survival and OS, and better quality of life.

Copies of Blueprint Medicines data presentations from the ASH annual meeting are available in the "SciencePublications and Presentations" section of the company's website at http://www.BlueprintMedicines.com.

About SM

SM is a rare disease driven by the KIT D816V mutation. Uncontrolled proliferation and activation of mast cells result in chronic, severe and often unpredictable symptoms for patients across the spectrum of SM. The vast majority of those affected have non-advanced (indolent or smoldering) SM, with debilitating symptoms that lead to a profound, negative impact on quality of life. A minority of patients have advanced SM, which encompasses a group of high-risk SM subtypes including aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia. In addition to mast cell activation symptoms, advanced SM is associated with organ damage due to mast cell infiltration and poor OS.

Debilitating symptoms associated with SM, including anaphylaxis, maculopapular rash, pruritis, brain fog, fatigue and bone pain, often persist despite treatment with a number of symptomatic therapies. Patients often live in fear of attacks, have limited ability to work or perform daily activities, or isolate themselves to protect against unpredictable triggers. Currently, there are no approved therapies that selectively inhibit D816V mutant KIT.

About AYVAKIT (avapritinib)

AYVAKIT (avapritinib) is a kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. For more information, visit http://www.AYVAKIT.com. This medicine is approved in Europe under the brand name AYVAKYT for the treatment of adults with unresectable or metastatic GIST harboring the PDGFRA D842V mutation.

AYVAKIT/AYVAKYT is not approved for the treatment of any other indication, including SM, in the U.S. by the FDA or in Europe by the European Commission, or for any indication in any other jurisdiction by any other health authority.

Blueprint Medicines is developing AYVAKIT globally for the treatment of advanced and indolent SM. The FDA granted breakthrough therapy designation to AYVAKIT for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematologic neoplasm and mast cell leukemia.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of AYVAKIT in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for AYVAKIT in the rest of the world.

AboutBlueprint Medicines

Blueprint Medicinesis a precision therapy company striving to improve human health. With a focus on genomically defined cancers, rare diseases and cancer immunotherapy, we are developing transformational medicines rooted in our leading expertise in protein kinases, which are proven drivers of disease. Our uniquely targeted, scalable approach empowers the rapid design and development of new treatments and increases the likelihood of clinical success. We have two approved precision therapies and are currently advancing multiple investigational medicines in clinical and pre-clinical development, along with a number of earlier-stage research programs. For more information, visit http://www.BlueprintMedicines.comand follow us on Twitter(@BlueprintMeds) andLinkedIn.

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, statements regarding plans, timelines and expectations for interactions with the FDA and other regulatory authorities; plans and timelines for submitting a supplemental new drug application to the FDA for AYVAKIT for the treatment of advanced SM; expectations regarding the potential benefits of AYVAKIT in treating patients with SM; andBlueprint Medicines'strategy, goals and anticipated milestones, business plans and focus. The words "aim," "may," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "estimate," "predict," "project," "potential," "continue," "target" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks and uncertainties related to the impact of the COVID-19 pandemic toBlueprint Medicines'business, operations, strategy, goals and anticipated milestones, includingBlueprint Medicines'ongoing and planned research and discovery activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products;Blueprint Medicines'ability and plans in establishing a commercial infrastructure, and successfully launching, marketing and selling current or future approved products, including AYVAKIT and GAVRETO (pralsetinib);Blueprint Medicines'ability to successfully expand the approved indications for AYVAKIT and GAVRETO or obtain marketing approval for AYVAKIT and GAVRETO in additional geographies in the future; the delay of any current or planned clinical trials or the development ofBlueprint Medicines'current or future drug candidates;Blueprint Medicines'advancement of multiple early-stage efforts;Blueprint Medicines'ability to successfully demonstrate the safety and efficacy of its drug candidates and gain approval of its drug candidates on a timely basis, if at all; the pre-clinical and clinical results forBlueprint Medicines'drug candidates, which may not support further development of such drug candidates; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials;Blueprint Medicines'ability to develop and commercialize companion diagnostic tests for its current and future drug candidates; and the success ofBlueprint Medicines'current and future collaborations, partnerships or licensing arrangements, includingBlueprint Medicines'global collaboration with Roche for the development and commercialization of GAVRETO. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" inBlueprint Medicines'filings with theSecurities and Exchange Commission(SEC), includingBlueprint Medicines'most recent Annual Report on Form 10-K, as supplemented by its most recent Quarterly Report on Form 10-Q and any other filings thatBlueprint Medicineshas made or may make with theSECin the future. Any forward-looking statements contained in this press release representBlueprint Medicines'views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. Except as required by law,Blueprint Medicinesexplicitly disclaims any obligation to update any forward-looking statements.

Reference

1Jennings SV, Slee VM, Zach, RM, et al. Patient Perceptions in Mast Cell Disorders. Immunol Allergy Clin North Am. 2018;38(3):505-525.

Trademarks

Blueprint Medicines, AYVAKIT, AYVAKYT, GAVRETO and associated logos are trademarks of Blueprint Medicines Corporation.

SOURCE Blueprint Medicines Corporation

http://www.blueprintmedicines.com

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Blueprint Medicines Data Presented at 62nd ASH Annual Meeting and Exposition Highlight Broad Commitment to Advance Patient Care in Systemic...

NEW YORK, Dec. 10, 2020 (GLOBE NEWSWIRE) -- BeyondSpring (the Company or BeyondSpring) (NASDAQ: BYSI), a global biopharmaceutical company focused on the development of innovative cancer therapies, today announced the new data from its Phase 3 PROTECTIVE-2 Study 106 demonstrating that plinabulin in combination with pegfilgrastim offers greater protection against chemotherapy-induced neutropenia (CIN) than the standard of care, pegfilgrastim alone. The study not only met the primary and key secondary objectives, as previously disclosed on Nov. 16, 2020, but also demonstrated that the combination was 53% more effective than pegfilgrastim alone in reducing the incidence of profound neutropenia (absolute neutrophil count or ANC < 0.1 x 10E9 cells/L), 21.6% vs. 46.4%, respectively, p=0.0001, in patients with breast cancer undergoing chemotherapy with TAC (docetaxel, doxorubicin, and cyclophosphamide). Profound neutropenia (PN) is a well-known risk factor to increase the rates of infection, febrile neutropenia (FN), and hospitalization among patients undergoing chemotherapy. Of clinical importance, the combination has shown to reduce the odds of having FN by 41% in comparison to pegfilgrastim, based on reduction of profound neutropenia.

It is clinically meaningful to reduce FN risk by 41% in the combination, compared to pegfilgrastim alone, which is the only major breakthrough advancement in CIN prevention in the last 30 years. The CIN protection from plinabulin added to pegfilgrastim, particularly in the first week of chemotherapy when 75% of CIN-related complications occur before the effect of pegfilgrastim kicks-in in Week 2, fills the treatment gap in current standard of care, said Douglas Blayney, M.D., Professor of Medicine at Stanford Medical School, and global PI for the plinabulin CIN studies. The combination of plinabulin with pegfilgrastim represents a major advancement in offering protection against CIN, with the potential to reduce FN risk, in the care of cancer patients.

The data were presented via a poster at the 2020 San Antonio Breast Cancer Symposium (SABCS): Superior and Clinically Meaningful Protection Against Profound Neutropenia with the Plinabulin/Pegfilgrastim (Plin/Peg) Combination versus Peg In Breast Cancer Patients ReceivingTAC Chemotherapy. Profound neutropenia, an exploratory endpoint representing the most severe form of CIN, is associated with significant risk to patients and may require antibacterial or antifungal prophylaxis [Flowers JCO 2013]. It is attributed to both febrile neutropenia (48%) and infection (50%) [Bodey Cancer 1978]. In BeyondSprings PROTECTIVE-2 studies, patients with profound neutropenia had close to nine times the risk of FN compared to patients with no profound neutropenia. The new data presented at SABCS included:

This trial is a global, multicenter, randomized, double-blinded study in patients with breast cancer undergoing myelosuppressive chemotherapy with TAC (docetaxel at 75 mg/m2, doxorubicin at 50 mg/m2, and cyclophosphamide at 500 mg/m2) for the evaluation of protection against CIN, comparing plinabulin (40 mg) in combination with pegfilgrastim (6 mg) in 111 patients to pegfilgrastim alone (6 mg) in 110 patients. On Day 1, they received TAC and plinabulin or placebo, and on Day 2, they received pegfilgrastim. Topline data from the Protective-2 Phase 3 trial were reported on November 16, 2020 highlighting that the study met its primary endpoint as well as key secondary endpoints.

It is well recognized that CIN is directly related to chemotherapys ability to kill rapidly dividing cells. Unfortunately, fast dividing neutrophils in the bone marrow are adversely affected regardless of the chemotherapy type. As a result, we believe these outcomes are universally applicable to any chemotherapy, and are independent of cancer types, added Gordon Schooley, Ph.D., BeyondSprings Chief Regulatory Officer. As both the U.S. FDA and China NMPA recently awarded BeyondSprings Plinabulin CIN program with Breakthrough Therapy Designation status based on the interim phase 3 data of PROTECTIVE-2, and the Company now completing the PROTECTIVE-2 trial with positive and consistent results to the interim, we are well on track to submit our NDA for CIN in Q1 2021. The improved CIN prevention benefit of the Plinabulin/G-CSF combination would have the potential for CIN prevention of the myelosuppressive effects of different chemotherapeutic agents in millions of patients with multiple tumor types.

Ramon Mohanlal, M.D., Ph.D., BeyondSprings Chief Medical Officer and Executive Vice President, Research and Development concluded, Plinabulin represents a new treatment paradigm for CIN prevention, an area wherein G-CSF has established efficacy, but with short-comings due to its delayed onset of action, next day dosing requirement, bone pain induction, and platelet count reduction. Plinabulin has a fast onset mechanism of action, without causing relevant bone pain or thrombocytopenia, and can be given on the same day as chemotherapy. Plinabulin added to G-CSF offers superior prevention of CIN, and has the potential to avoid life-threatening infections and to improve short-term and long-term survival. Plinabulins anticancer activity from its immune-enhancing mechanism of action, together with its CIN preventive effects, has the potential to become a universal add-on to anti-cancer treatments in general.

The above data are available on BeyondSpringswebsite in the Posters section.

About PlinabulinPlinabulin, BeyondSprings lead asset, is a differentiated immune and stem cell modulator. Plinabulin is currently in late-stage clinical development to increase overall survival in cancer patients, as well as to alleviate chemotherapy-induced neutropenia (CIN). The durable anticancer benefits of Plinabulin have been associated with its effect as a potent antigen-presenting cell (APC) inducer (through dendritic cell maturation) and T-cell activation (Chem and Cell Reports, 2019). Plinabulins CIN data highlight the ability to boost the number of hematopoietic stem / progenitor cells (HSPCs), or lineage-/cKit+/Sca1+ (LSK) cells in mice. Effects on HSPCs could explain the ability of Plinabulin not only to treat CIN, but also to reduce chemotherapy-induced thrombocytopenia and increase circulating CD34+ cells in patients.

About CINPatients receiving chemotherapy typically develop chemotherapy-induced neutropenia (CIN), a severe side effect that increases the risk of infection with fever (also called febrile neutropenia, or FN), which necessitates ER/hospital visits. The updated National Comprehensive Cancer Network (NCCN) guidelines expanded the use of prophylactic G-CSFs, such as pegfilgrastim, to include not only high- risk patients (chemo FN rate>20%), but also intermediate-risk patients (FN rate between 10-20%) to avoid hospital/ER visits during the COVID-19 pandemic. The revision of the NCCN guidelines effectively doubles the addressable market of patients who may benefit from treatment with plinabulin, if approved, to approximately 440,000 cancer patients in the U.S. annually. Plinabulin is designed to provide protection against the occurrence of CIN and its clinical consequences in week 1, for early onset of action after chemotherapy. CIN is the primary dose-limiting toxicity in cancer patients who receive chemotherapy treatment.

About BeyondSpringBeyondSpring is a global, clinical-stage biopharmaceutical company focused on the development of innovative cancer therapies. BeyondSprings lead asset, plinabulin, a first-in-class agent as an immune and stem cell modulator, is in a Phase 3 global clinical trial as a direct anticancer agent in the treatment of non-small cell lung cancer (NSCLC) and Phase 3 clinical programs in the prevention of CIN. The U.S. FDA granted Breakthrough Therapy designation to plinabulin for concurrent administration with myelosuppressive chemotherapeutic regimens in patients with non-myeloid malignancies for the prevention of chemotherapy-induced neutropenia (CIN). BeyondSpring has strong R&D capabilities with a robust pipeline in addition to plinabulin, including three immuno-oncology assets and a drug discovery platform using the protein degradation pathway, which is being developed in a subsidiary company, Seed Therapeutics, Inc. The Company also has a seasoned management team with many years of experience bringing drugs to the global market. BeyondSpring is headquartered in New York City.

Cautionary Note Regarding Forward-Looking StatementsThis press release includes forward-looking statements that are not historical facts. Words such as "will," "expect," "anticipate," "plan," "believe," "design," "may," "future," "estimate," "predict," "objective," "goal," or variations thereof and variations of such words and similar expressions are intended to identify such forward-looking statements. Forward-looking statements are based on BeyondSpring's current knowledge and its present beliefs and expectations regarding possible future events and are subject to risks, uncertainties and assumptions. Actual results and the timing of events could differ materially from those anticipated in these forward-looking statements as a result of several factors including, but not limited to, difficulties raising the anticipated amount needed to finance the Company's future operations on terms acceptable to the Company, if at all, unexpected results of clinical trials, delays or denial in regulatory approval process, results that do not meet our expectations regarding the potential safety, the ultimate efficacy or clinical utility of our product candidates, increased competition in the market, and other risks described in BeyondSprings most recent Form 20-F on file with the U.S. Securities and Exchange Commission. All forward-looking statements made herein speak only as of the date of this release and BeyondSpring undertakes no obligation to update publicly such forward-looking statements to reflect subsequent events or circumstances, except as otherwise required by law.

Media Contacts

Investor Contact:Ashley R. RobinsonLifeSci Advisors, LLC+1 617-430-7577arr@lifesciadvisors.com

Media Contact:Darren Opland, Ph.D.LifeSci Communications+1 646-627-8387darren@lifescicomms.com

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BeyondSpring Announces New Positive PROTECTIVE-2 Phase 3 Registrational Trial Results at the 2020 San Antonio Breast Cancer Symposium - BioSpace

MISSISSAUGA, ON, Dec. 10, 2020 /CNW/ -Gilead Sciences Canada, Inc. (Gilead Canada) announced today that YESCARTA(axicabtagene ciloleucel) is now available in Ontario as a treatment for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.i YESCARTA will be manufactured by Kite, a Gilead Company (Kite) at its commercial manufacturing facility in El Segundo, California.

YESCARTA is a chimeric antigen receptor T-cell (CAR T) therapy, an individualized method of treatment that harnesses the power of the body's own immune system to target cancer cells. In CAR T therapy, T cells (a type of white blood cell) are removed from a patient (a process called apheresis) and modified so they can recognize and respond to a specific antigen, which is identified on cancer cells and signals cell death.ii This cell therapy can induce a complete response (no detectable cancer) in a proportion of patients with relapsed or refractory DLBCL and PMBCL, which are aggressive forms of non-Hodgkin lymphoma (NHL).iii Eligible patients in Ontario now have the option to be treated with YESCARTA at Princess Margaret Cancer Centre and The Ottawa Hospital.

"Today's announcement means that patients now have a much-needed new treatment option, which offers an exciting and innovative way to treat these types of blood cancer," saidMelissa Koomey, Vice President and General Manager, Gilead Canada. "Gilead will continue to work to provide final site certification to a number of specialized centres across Canada enabling them to make YESCARTA available to appropriate patients."

DLBCL is the most common form of NHL (a group of cancers that originate primarily in types of white blood cells)iv and accounts for approximately 30 per cent of newly diagnosed cases.v Based on previous rates of diagnosis, in Canada it is estimated that up to 4,000 new cases of DLBCL were diagnosed in 2019.vi,vii The prognosis for relapsed or refractory adult patients is very poor, with a median survival of just six months.viiiGilead Canada received approval for YESCARTA in Canada in February, 2019.

"CAR T therapy is a personalized treatment option that could offer a significant benefit to patients with certain rare and aggressive forms of relapsed or refractory non-Hodgkin lymphoma," said Dr. John Kuruvilla, MD, FRCPC, ZUMA-1 Investigator and Hematologist in the Division of Medical Oncology and Hematology at the Princess Margaret Cancer Centre. "For these patients, the prognosis is very poor, even a year or less. With access to YESCARTA, they have a new andpotentially life changing opportunity."

The approval of YESCARTA was based on one-year follow-up data (median of 15.4 months) from the pivotal ZUMA-1 trial of axicabtagene ciloleucel in adult patients with refractory large B-cell lymphoma. Data from the two-year (median of 27.1 months) follow-up of ZUMA-1 showed that 74 per cent (n=75/101) of adult patients with relapsed or refractory large B-cell lymphoma treated with a single infusion of YESCARTA responded to therapy, with 54 per cent achieving a complete response.ix

In the ZUMA-1 trial the most common Grade 3 or higher adverse reactions include encephalopathy (30%), unspecified pathogen infection (19%), hypotension (15%), fever (14%), cytokine release syndrome (12%), hypoxia (10%), bacterial infection (8%), aphasia (7%), arrhythmia (6%), viral infection (6%), delirium (6%), and hypertension (6%).xGrade 3 or higher prolonged cytopenias (still present at Day 30 or with an onset at Day 30 or beyond) included neutropenia (31%), thrombocytopenia (27%), and anemia (17%).xi

"Today's announcement offers new hope for patients with certain types of relapsed and refractory lymphomas, who previously faced a dire prognosis," said Antonella Rizza, CEO at Lymphoma Canada. "By taking this step, the Ontario government is ensuring Canadians in this province have access to this new and potentially transformative treatment option."

In the ZUMA-1 pivotal trial, Kite demonstrated a 99 per cent manufacturing success rate with a median manufacturing turnaround time of 17 daysxii.

Important Safety InformationThe YESCARTA Product Monograph has aSERIOUS WARNINGS AND PRECAUTIONS BOX regarding the risks of:

YESCARTA should be administered by experienced health professionals at specialized treatment centres.xv

For all important safety information for YESCARTA, including contraindications, warnings and precautions, adverse reactions and drug interactions, please see the Canadian Product Monograph at http://www.gilead.ca.

About Kite Kite, a Gilead Company, is a biopharmaceutical company based in Santa Monica, California. Kite is engaged in the development of innovative cancer immunotherapies. The company is focused on chimeric antigen receptor and T cell receptor engineered cell therapies. For more information on Kite, please visit http://www.kitepharma.com.

About Gilead Sciences Gilead Sciences, Inc. is a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines in areas of unmet medical need. The company strives to transform and simplify care for people with life-threatening illnesses around the world. Gilead has operations in more than 35 countries worldwide, with headquarters in Foster City, California. Gilead Sciences Canada, Inc. is the Canadian affiliate of Gilead Sciences, Inc., and was established in Mississauga, Ontario, in 2006. For more information on Gilead Sciences, please visit the company's website at http://www.gilead.com.

Forward-Looking StatementThis press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk thatphysicians and patients may not see the benefits of YESCARTAas a treatment option for the indications for which it is approved; the ability to provide final site certification to specialized centres across Canada enabling them to make YESCARTA available to appropriate patients in the anticipated timelines or at all;the ability of Kite to continue to manufacture YESCARTA at the success rates experienced during clinical trials; and the possibility of unfavorable results from ongoing and additional clinical trials involving YESCARTA. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter endedSeptember 30, 2020 as filed with theU.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

YESCARTA, KITE PHARMA and the KITE LOGO, are trademarks of Kite Pharma, Inc. GILEAD, and the GILEAD LOGO are trademarks of Gilead Sciences, Inc., or its related companies.

Learn more about Gilead at http://www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000. For more information on Kite, please visit the company's website atwww.kitepharma.com. Follow Kite on social media on Twitter (@KitePharma) and LinkedIn.

_________________

i YESCARTAproduct monograph, February 13, 2019, revised March 18, 2020 (www.gilead.ca).

iiLeukemia & Lymphoma Society (LLS). Chimeric antigen receptor (CAR) T-cell therapy. 2019. Available at: https://www.lls.org/treatment/types-of-treatment/immunotherapy/chimeric-antigen-receptor-car-t-cell-therapy. Accessed March 2020.

iii Locke F. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. The Lancet Oncol. 2019 Jan; 20(1):31-42.

iv Lymphoma Research Foundation (LRF). Diffuse Large B-Cell Lymphoma (DLBCL). 2018. Available at: https://lymphoma.org/wp-content/uploads/2018/05/LRF_FACTSHEET_DIFFUSE_LRG_BCELL_LYMPHOMA_DLBCL.pdf. Accessed March 2020.

v Menon M. et al. The Histological and Biological Spectrum of Diffuse Large B-cell Lymphoma in the WHO Classification. Cancer J. 2012 Sept;18(5):411420.

vi Menon M. et al. The Histological and Biological Spectrum of Diffuse Large B-cell Lymphoma in the WHO Classification. Cancer J. 2012 Sept;18(5):411420.

viiCanadian Cancer Society: Non-Hodgkin Lymphoma statistics. Available at: https://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/statistics/?region=on Accessed March 2020

viii Crump M. et al, Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017 Oct. 130(16): 18001808.

ix YESCARTAproduct monograph, February 13, 2019, revised March 18, 2020 (www.gilead.ca).

xIBID

xi IBID

xii Neelapu, SS, Locke, FL, Bartlett, NL, et al. New England Journal of Medicine. "Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma." Available at: http://www.bloodjournal.org/content/130/16/1800 https://www.nejm.org/doi/full/10.1056/NEJMoa1707447/. Accessed: May 14, 2020.

xiii YESCARTAproduct monograph, February 13, 2019, revised March 18, 2020 (www.gilead.ca).

xiv IBID

xv IBID

SOURCE Gilead Sciences Canada, Inc.

View original post here:
Kite's YESCARTA (Axicabtagene Ciloleucel) Reimbursed in Ontario for the Treatment of Certain Types of Aggressive Non-Hodgkin Lymphoma - BioSpace

CAMBRIDGE, Mass.--(BUSINESS WIRE)--bluebird bio, Inc. (Nasdaq: BLUE) announced that new data from Group C of its ongoing Phase 1/2 HGB-206 study of investigational LentiGlobin gene therapy (bb1111) for adult and adolescent patients with sickle cell disease (SCD) show a complete elimination of severe VOEs and VOEs between six and 24 months of follow-up. These data are being presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, taking place virtually from December 5-8, 2020.

Now with more than two years of data, we continue to observe promising results in our studies of LentiGlobin for SCD that further illustrate its potential to eliminate the symptoms and devastating complications of sickle cell disease. Consistently achieving the complete resolution of severe vaso-occlusive events (VOEs) and VOEs between Month 6 and Month 24 follow-up is unprecedented other than with allogeneic stem cell transplantation. Importantly, our data show the potential for LentiGlobin for SCD to produce fundamentally disease-modifying effects with sustained pancellular distribution of gene therapy-derived anti-sickling HbAT87Q and improvement of key markers of hemolysis that approach normal levels, said David Davidson, M.D., chief medical officer, bluebird bio. In addition to these clinical outcomes, for the first time with a gene therapy we now have patient-reported outcomes through the validated PROMIS-57 tool, showing reduction in pain intensity at 12 months after treatment with LentiGlobin for SCD. These results provide insight into the potential real-life impact LentiGlobin for SCD may offer patients.

SCD is a serious, progressive and debilitating genetic disease. In the U.S., the median age of death for someone with sickle cell disease is 43 46 years. SCD is caused by a mutation in the -globin gene that leads to the production of abnormal sickle hemoglobin (HbS). HbS causes red blood cells to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and unpredictable, painful VOEs.

In the HGB-206 study of LentiGlobin for SCD, VOEs are defined as episodes of acute pain with no medically determined cause other than a vaso-occlusion, lasting more than two hours and severe enough to require care at a medical facility. This includes acute episodes of pain, acute chest syndrome (ACS), acute hepatic sequestration and acute splenic sequestration. A severe VOE requires a 24-hour hospital stay or emergency room visit or at least two visits to a hospital or emergency room over a 72-hour period, with both visits requiring intravenous treatment.

LentiGlobin for SCD was designed to add functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once patients have the A-T87Q-globin gene, their red blood cells can produce anti-sickling hemoglobin (HbAT87Q) that decreases the proportion of HbS, with the goal of reducing sickled red blood cells, hemolysis and other complications.

As a hematologist, I regularly see the debilitating effects of pain events caused by sickle cell disease. Pain has an overwhelmingly negative impact on many facets of my patients lives and can lead to prolonged hospitalizations, said presenting study author Alexis A. Thompson, M.D., professor of pediatrics at Northwestern University Feinberg School of Medicine and head of hematology at Ann and Robert H. Lurie Childrens Hospital of Chicago. The results observed with LentiGlobin gene therapy for SCD include the complete elimination of severe vaso-occlusive pain episodes, which is certainly clinically meaningful, but also for the first time, we have documented patients reporting that they are experiencing improved quality of life. This degree of early clinical benefit is extraordinarily rewarding to observe as a provider."

As of the data cut-off date of August 20, 2020, a total of 44 patients have been treated with LentiGlobin for SCD in the HGB-205 (n=3) and HGB-206 (n=41) clinical studies. The HGB-206 total includes: Groups A (n=7), B (n=2) and C (n=32).

HGB-206: Group C Updated Efficacy Results

The 32 patients treated with LentiGlobin for SCD gene therapy in Group C of HGB-206 had up to 30.9 months of follow-up (median of 13.0; min-max: 1.1 30.9 months).

In patients with six or more months of follow-up whose hemoglobin fractions were available (n=22), median levels of gene therapy-derived anti-sickling hemoglobin, HbAT87Q, were maintained with HbAT87Q contributing at least 40% of total hemoglobin at Month 6. At last visit reported, total hemoglobin ranged from 9.6 15.1 g/dL and HbAT87Q levels ranged from 2.7 8.9 g/dL. At Month 6, the production of HbAT87Q was associated with a reduction in the proportion of HbS in total hemoglobin; median HbS was 50% and remained less than 60% at all follow-up timepoints. All patients in Group C were able to stop regular blood transfusions by three months post-treatment and remain off transfusions as of the data cut-off.

Nineteen patients treated in Group C had a history of severe VOEs, defined as at least four severe VOEs in the 24 months prior to informed consent (annualized rate of severe VOE min-max: 2.0 10.5 events) and at least six months follow-up after treatment with LentiGlobin for SCD. There have been no reports of severe VOEs in these Group C patients following treatment with LentiGlobin for SCD. In addition, all 19 patients had a complete resolution of VOEs after Month 6.

Hemolysis Markers

In SCD, red blood cells become sickled and fragile, rupturing more easily than healthy red blood cells. The breakdown of red blood cells, called hemolysis, occurs normally in the body. However, in sickle cell disease, hemolysis happens too quickly due to the fragility of the red blood cells, which results in hemolytic anemia.

Patients treated with LentiGlobin for SCD in Group C demonstrated near-normal levels in key markers of hemolysis, which are indicators of the health of red blood cells. Lab results assessing these indicators were available for the majority of the 25 patients with 6 months of follow-up.

The medians for reticulocyte counts (n=23), lactate dehydrogenase (LDH) levels (n=21) and total bilirubin (n=24) continued to improve compared to screening values and stabilized by Month 6. In patients with Month 24 data (n=7), these values approached the upper limit of normal by Month 24. These results continue to suggest that treatment with LentiGlobin for SCD may improve biological markers to near-normal levels for SCD.

Pancellularity

As previously reported, assays were developed by bluebird bio to enable the detection of HbAT87Q and HbS protein in individual red blood cells, as well as to assess if HbAT87Q was pancellular, or present throughout all of a patients red blood cells. In 25 patients with at least six months of follow-up, on average, more than 80% of red blood cells contained HbAT87Q, suggesting near-complete pancellularity of HbAT87Q distribution and with pancellularity further increasing over time.

HGB-206: Improvements in Health-Related Quality of Life

Health-related quality of life (HRQoL) findings in Group C patients treated with LentiGlobin for SCD in the HGB-206 study were generated using the Patient Reported Outcomes Measurement Information System 57 (PROMIS-57), a validated instrument in SCD.

Data assessing pain intensity experienced by nine Group C patients were analyzed according to baseline pain intensity scores relative to the general population normative value: 2.6 on a scale of 0-10, where 10 equals the most intense pain. Data were assessed at baseline, Month 6 and Month 12.

Of the five patients with baseline scores worse than the population normative value average, four demonstrated clinically meaningful reductions in pain intensity at Month 12; the group had a mean score of 6.0 at baseline and a mean score of 2.4 at Month 12. Of the four patients with better than or near population normative values at baseline, two reported improvement and two remained stable with a mean score of 2.3 at baseline and 0.8 at Month 12.

HGB-206: Group C Safety Results

As of August 20, 2020, the safety data from Group C patients in HGB-206 remain generally consistent with the known side effects of hematopoietic stem cell collection and myeloablative single-agent busulfan conditioning, as well as underlying SCD. One non-serious, Grade 2 adverse event (AE) of febrile neutropenia was considered related to LentiGlobin for SCD. There were no serious AEs related to LentiGlobin for SCD.

One patient with significant baseline SCD-related and cardiopulmonary disease died 20 months post-treatment; the treating physician and an independent monitoring committee agreed his death was unlikely related to LentiGlobin for SCD and that SCD-related cardiac and pulmonary disease contributed.

LentiGlobin for SCD Data at ASH

The presentation of HGB-206 Group C results and patient reported outcomes research are now available on demand on the ASH conference website:

About HGB-206

HGB-206 is an ongoing, Phase 1/2 open-label study designed to evaluate the efficacy and safety of LentiGlobin gene therapy for sickle cell disease (SCD) that includes three treatment cohorts: Groups A (n=7), B (n=2) and C (n=32). A refined manufacturing process designed to increase vector copy number (VCN) and further protocol refinements made to improve engraftment potential of gene-modified stem cells were used for Group C. Group C patients also received LentiGlobin for SCD made from HSCs collected from peripheral blood after mobilization with plerixafor, rather than via bone marrow harvest, which was used in Groups A and B of HGB-206.

About LentiGlobin for SCD (bb1111)

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

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

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

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

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

About bluebird bio, Inc.

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

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

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

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

LentiGlobin and bluebird bio are trademarks of bluebird bio, Inc.

Forward-Looking Statements

This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: regarding the potential for LentiGlobin for Sickle Cell Disease to treat SCD; the risk that the efficacy and safety results from our prior and ongoing clinical trials will not continue or be repeated in our ongoing or planned clinical trials; the risk that the current or planned clinical trials of our product candidates will be insufficient to support regulatory submissions or marketing approval in the United States and European Union; the risk that regulatory authorities will require additional information regarding our product candidates, resulting in delay to our anticipated timelines for regulatory submissions, including our applications for marketing approval; and the risk that any one or more of our product candidates, will not be successfully developed, approved or commercialized. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in our most recent Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

Original post:
Treatment with Investigational LentiGlobin Gene Therapy for Sickle Cell Disease (bb1111) Results in Complete Elimination of SCD-Related Severe...

Cognitive and emotional functions in pediatric patients should not be overlooked when assessing potential for sickle cell disease self-management practices and healthcare utilization.

A study, presented at the American Society of Hematology (ASH) 2020 Annual Meeting, specifically investigated the extent to which these functions contribute to rates of pain-related visits to the hospital or emergency department.

A team led by Zaria Williams, Howard University College of Medicine, conducted an analysis of pediatric patients representing all genotypes of sickle cell disease. Using existing data from a previous study on computerized working memory training, they gathered cognitive abilities, socioeconomic status, and emotional functioning to determine whether such variables were predictive of healthcare utilization.

Cognitive measures were based on the Wechsler Intelligence Scale for Children (WISC-V) Full Scale IQ as well as a computerized cognitive assessment.

Williams and team measured emotional functioning using the Worry and Emotions domains of the child- and parent-rated Pediatric Quality of Life Inventory Sickle Cell Disease Module.

And finally, they measured heartcare utilization according to chart reviewwhich they separated into emergency department visits for pain and hospitalizations for pain 1 year and 3 years following study enrollment.

Thus, they assessed a total of 112 children, where the mean age was 10.61 years. A majority (58%) were female. Further, 74% had sickle cell anemia (HbSS or HbS0 thalassemia).

For the entire population, the median number of emergency department visits was 1 across 1 year (IQR, 2) following enrollment. After 3 years, the median was 3 visits (IQR, 6).

In terms of hospital admissions, the median number of visits was 0 after 1 year (IQR, 1) and 1 after 3 years (IQR, 4).

Cognitive, Emotional Abilities and Healthcare Visits

Linear regression models indicated that there was a significant association between attentional abilities and emergency department visits and hospitalizations for painboth for 1 year and 3 years following enrollment (P<.009 for both).

According to the investigators, better performance on the Constate attention task was associated with fewer emergency department visits and hospitalizations.

Furthermore, child-rated emotional quality of life significantly predicted emergency department visits for pain over 1 year (P = .004) and hospitalizations for pain over 3 years (P = .013). Similarly, higher emotional quality of life was predictive of fewer emergency department and hospital visits.

Parent-rated emotional quality of life was predictive of hospitalizations for pain over 3 years (P = .020).

Lastly, the investigators noted that neither sickle cell disease genotype nor socioeconomic status had any significant influence on healthcare utilization.

Results demonstrate that childrens cognitive and emotional functioning play an important role in pain management and should be an integral part of comprehensive pain management plans for children with sickle cell disease, they wrote.

Implications and New Perspectives on Sickle Cell Care

Williams and colleagues indicated that attentional abilities appeared to be a reliable predictor of pain-related healthcare utilization. Poor attention may make it difficult to implement strategies that could distract the child from pain.

Further, these findings can be suggestive of the fact that children with poor attention may struggle with behavioral aspects of disease-self management, such as medication adherence and avoidance of pain triggers.

They believed that these considerations should be taken seriously in the treatment of this already high-risk population.

Clinicians and researchers should consider cognitive and emotional factors when evaluating risk for pain in sickle cell disease and incorporate these factors when developing strategies to reduce healthcare utilization and costs, the team concluded.

The study, Cognitive and Emotional Factors and Pain-Related Outcomes in Youth with Sickle Cell Disease, was presented at ASH 2020.

Read more:
Cognitive, Emotional Measures Linked to Sickle Cell Healthcare Utilization - MD Magazine

Identification of key oncogenic drivers and the development of targeted therapies with clinical activity in patients harboring actionable mutations have revolutionized the treatment paradigm in nonsmall cell lung cancer (NSCLC), redirecting attention toward advances in biomarker testing methodologies. This new focus is poised to foster granular refinement of precise, targeted treatment of lung tumors.

Advances in NSCLC research have enabled an understanding of the disease as a collection of molecular subgroups. The proliferation of alteration-matched therapies specific to these subgroups is a prime example of a precision medicine approach. In addition to oncogenic driver mutations, therapeutic response biomarkers have been identified, such as PD-L1 expression as a predictor of immunotherapy efficacy.

Underscoring the importance of biomarker-guided treatment approaches, guidelines for molecular testing in NSCLC include an extensive list of alterations, such as sensitizing EGFR mutations and ALK gene fusions.1,2 The list continues to expand beyond these established canonical markers, with the addition of variants such as MET exon 14 skipping mutations and tumor mutational burden. In fact, the FDA recently approved therapies specific for tumors with these molecular characteristics.3,4

The rapid pace of biomarker discovery, characterization of molecular subtypes of NSCLC, development of matched targeted therapies, and regulatory approval of companion diagnostic tests has accelerated progress in the delivery of optimal care for patients with advanced NSCLC. Areas where continued optimization is particularly emphasized include determining which type of sample(s) should be tested, which biomarkers should be analyzed in different patient subsets, and which assays are most appropriate for specific (sets of) markers, as well as logistical and administrative factors, such as turnaround times and cost/reimbursement considerations.1,5,6

As biomarker testing in NSCLC evolves, investigators continue to evaluate testing approaches with the goal of standardizing the process of oncogenic driver identification.

At the 2020 Molecular Analysis for Precision Oncology (MAP) Virtual Congress, held October 9 to 10, 2020, presentations focused on recent developments in molecular testing, including the results of studies comparing testing methods for aberrations in the MET and NTRK genes.

MET Exon 14 Skipping

Gain-of-function alterations in MET, which encodes a receptor tyrosine kinase, drive oncogenesis. One such alteration with important implications for NSCLC is MET exon 14 skipping, resulting from several types of mutation in either exon 14 itself, the adjacent introns, or the flanking splice sites. Regardless, the effect is the same: a critical ubiquitination site is lost, which leads to MET protein accumulation and activation, enhancing MET pathway signal transduction and culminating in tumorigenesis. Previously, immunohistochemistry was typically performed to detect MET overexpression due to copy number changes. However, next-generation sequencing (NGS) is now the preferred testing method because it can also identify MET exon 14 skipping mutations, the primary driver of oncogenesis.7

MET exon 14 skipping mutations are actionable because the resultant protein is responsive to MET inhibition using tyrosine kinase inhibitors (TKIs) such as capmatinib (Tabrecta),7 which was approved in May 2020 for use in adult patients with metastatic NSCLC harboring a MET exon 14 skipping mutation.3 Compared with their sensitivity to specific TKIs, this subset of patients has exhibited lower rates of response to immunotherapy despite frequent tumor expression of PD-L1,8 suggesting a dual predictive role for the MET exon 14 skipping mutation as a biomarker.

In a study presented at MAP 2020, tumor samples from patients with NSCLC and no other driver mutations were tested for MET exon 14 skipping mutations over a period of 14 months. The investigators compared 2 DNA-based methods: NGS on the Ion Proton platform using AmpliSeq technology and fragment analysis using polymerase chain reaction (PCR) and size-based electrophoretic separation of the amplicons for detection of large deletions.9

Of the 87 patient samples tested, 13 were determined to have a MET exon 14 skipping alteration, with 5 harboring splice variants and 8 carrying deletions affecting the splice site. Two of these deletions were large, spanning 41 and 66 base pairs; they were detected by fragment analysis but not NGS. Although NGS is widely considered superior to single-gene assays, these data indicate that it may have limitations in detecting specific alterations and that complementary methods or large-coverage intron screening could be an alternative for optimal detection of MET alterations to inform selection of first-line treatment, according to lead study author Romain Loyaux, from the Molecular Oncology Department of Georges-Pompidou European HospitalAPHP in Paris, France.

Commenting on the failure of the NGS assay to detect large MET exon 14 deletions, Loyaux stated that fragment analysis is a cheap and robust method to detect large deletions, especially when no RNA is available (FIGURE).9-11 He noted that anchored, multiplex, targeted RNA-based NGS, like the technology developed by the Archer company, may be a good alternative when RNA is available; however, it has a 20% failure rate.12

NTRK Fusion Detection

Fusions involving the NTRK genes, which encode a family of receptor tyrosine kinases, result in a constitutively activated chimeric protein that promotes oncogenesis and therefore, can be therapeutically targeted with TKIs.7 Two FDA-approved TKIs, entrectinib (Rozlytrek) and larotrectinib (Vitrakvi), have activity in NTRK fusionpositive solid tumors.13,14

Broad, hybrid-capture DNA-based NGS, with RNA-based anchored multiplex PCR as an adjunct, are currently the primary methods of detecting NTRK gene fusions in patients with lung cancer.7 The availability of entrectinib and larotrectinib will likely foster further development of NTRK fusion detection methods for use in routine clinical practice.

A recent study presented at MAP 2020 evaluated the analytical performancenamely, sensitivity, specificity, and precisionof 3 commonly available RNA-based NGS assays. The assays examined were TruSight Oncology 500 (TSO500) by Illumina, Oncomine Focus Assay (OFA) by Thermo Fisher Scientific, and Fusion- Plex Lung (AFL) by Archer.15

The limits of sensitivity and precision were assessed using droplet digital PCR with admixtures of both NTRK fusionpositive and negative samples, whereas specificity was evaluated using NTRK fusionnegative clinical samples. The data showed that all 3 NGS assays successfully detected NTRK fusions; however, technical differences between the assays may impact their performance. For instance, although all tested assays demonstrated strong specificity, the sample metrics were variable. Quality control (QC) success rates for OFA and TSO500 were 83% and 77%, respectively, but only 43% of samples on AFL passed all assay QC metrics. Notably, the different assays missed specific NTRK fusions; OFA failed to detect NTRK1-LMNA, NTRK1-TFG, and NTRK2- PAN3, and TSO500 failed to report NTRK3-ETV6 (E5N14) and NTRK3-ETV6 (E5N15).15

Clinical Utility of NGS Panels of Different Sizes

It has been established that multigene panels are superior to single-gene assays for biomarker testing in NSCLC2; however, data to inform clinicians selection of specific NGS gene panels have been lacking.

In a recent study presented at MAP 2020, a literature review was conducted to compare 2 commercially available DNA-based NGS gene panels: the Ion AmpliSeq Cancer Hotspot Panel, covering hotspots in 50 genes (Panel 50); and the FoundationOne panel, covering the complete exons of 315 genes (Panel 315). The clinical utility of each panel was determined based on the number of detectable actionable alterations in various solid tumor types that it contained. The data showed a substantial gain in actionability using the larger gene panel, which matched more actionable genetic mutations to FDA-approved or experimental drugs; the number of actionable alterations in various solid tumor types using Panel 315 was a median 50% higher compared with Panel 50 (t test, P <.001). The authors attributed this gain to the inclusion of more genes related to homologous recombination repair deficiency and microsatellite instability/immunotherapy response in the larger panel.16

In the current era of precision medicine in lung cancer, defined histological subtyping, oncogenic driver testing, and analysis of tumor PD-L1 expression/immunotherapy sensitivity are crucial steps prior to therapeutic decision-making in NSCLC. As additional targeted agents are investigated in clinical trials and the incidence of their molecular targets are characterized in patient populations, expanded molecular testing may become necessary.

Molecular pathologists will continue to play an integral role in the continuum of care in NSCLC, from diagnosis to clinical decision-making based on biomarker detection. Molecular testing is likely to expand rapidly, and additional molecular subtypes will be identified that help match more patients with the optimal targeted therapies, providing highly personalized treatment plans.

Details of analytical procedures and assays will continue to be refined.17 By combining defined sets of biomarkers with appropriate protocols for collecting NSCLC samples and optimized methods for assessing specific changes, clinicians will be able to actualize the promise of precision medicine for patients with this challenging malignancy.

References:

1. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321-346. doi:10.5858/arpa.2017-0388-CP

2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 8.2020. Accessed October 26, 2020. https://bit.ly/2TKomAj

3. FDA grants accelerated approval to capmatinib for metastatic nonsmall cell lung cancer. FDA. May 6, 2020. Accessed November 2, 2020. https://bit.ly/360o7Xg

4. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA. June 16, 2020. Accessed November 2, 2020. https://bit.ly/2HWB64q

5. Smeltzer MP, Wynes MW, Lantuejoul S, et al. The International Association for the Study of Lung Cancer global survey on molecular testing in lung cancer. J Thorac Oncol. 2020;15(9):1434-1448. doi:10.1016/j.jtho.2020.05.002

6. Wempe MM, Stewart MD, Glass D, et al. A national assessment of diagnostic test use for patients with advanced NSCLC and factors influencing physician decision-making. Am Health Drug Benefits. 2020;13(3):110-119

7. Sabari JK, Santini F, Bergagnini I, Lai WV, Arbour KC, Drilon A. Changing the therapeutic landscape in non-small cell lung cancers: the evolution of comprehensive molecular profiling improves access to therapy. Curr Oncol Rep. 2017;19(4):24. doi:10.1007/s11912-017-0587-4

8. Sabari JK, Montecalvo J, Chen R, et al. PD-L1 expression and response to immunotherapy in patients with MET exon 14-altered non-small cell lung cancers (NSCLC). J Clin Oncol. 2017;35(suppl 15):8512. doi:10.1200/JCO.2017.35.15_suppl.8512

9. Loyaux R, Blons H, Garinet S, Urban P, Leger C, Bastide M. MET exon 14 screening strategy: how not to miss large deletions. Ann Oncol. 2020;31(suppl 5): S1217-S1239. doi:10.1016/j.annonc.2020.08.2163

10. Pruis MA, Geurts-Giele WRR, von der TJH, et al. Highly accurate DNAbased detection and treatment results of MET exon 14 skipping mutations in lung cancer. Lung Cancer. 2020;140:46-54. doi:10.1016/j.lungcan.2019.11.010

11. Davies KD, Lomboy A, Lawrence CA, et al. DNA-based versus RNAbased detection of MET exon 14 skipping events in lung cancer. J Thorac Oncol. 2019;14(4):737-741. doi:10.1016/j.jtho.2018.12.020

12. Cohen D, Hondelink LM, Solleveld-Westerink N, et al. Optimizing mutation and fusion detection in NSCLC by sequential DNA and RNA sequencing. J Thorac Oncol. 2020;15(6):1000-1014. doi:10.1016/j.jtho.2020.01.019

13. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA. Published August 15, 2019. Accessed October 28, 2020. https://bit.ly/3mPhUEB

14. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Published November 26, 2018. Accessed October 28, 2020. https://bit.ly/381dXZe

15. Bormann Chung C, Lee J, Barritault M, et al. Evaluating targeted next-generation sequencing (NGS) assays and reference materials for NTRK fusion detection. Ann Oncol. 2020;31(suppl 5):S1221. doi:10.1016/j.annonc.2020.08.2172

16. zdemir B, Charrier M, Gerard CL, et al. Comparison of the clinical utility of two different size next generation sequencing (NGS) gene panels for solid tumours. Ann Oncol. 2020;31(suppl 5):S1219. doi:10.1016/j.annonc.2020.08.2166

17. Pennell NA, Arcila ME, Gandara DR, West H. Biomarker testing for patients with advanced non-small cell lung cancer: real-world issues and tough choices. Am Soc Clin Oncol Educ Book. 2019;39:531-542. doi:10.1200/EDBK_237863

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Increased Attention on Testing for Oncogenic Drivers in NSCLC Advances the Promise of Precision Medicine - Targeted Oncology

Angiocrine Bioscience Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to AB-205

About Regenerative Medicine Advanced Therapy (RMAT) DesignationEstablished under the 21st Century Cures Act, the RMAT designation was established to facilitate development and expedite review of cell therapies and regenerative medicines intended to treat serious or life-threatening diseases or conditions. Advantages include the benefits of the FDA's Fast Track and Breakthrough Therapy Designation programs, such as early interactions with the FDA to discuss potential surrogate or intermediate endpoints to support accelerated approval.

About HDT-AHCT High-dose therapy and autologous hematopoietic cell transplantation (HDT-AHCT) is considered a standard-of-care therapy for patients with aggressive systemic Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).Although efficacious and considered a potential cure, HDT-AHCT is associated with severe regimen-related toxicities (SRRT) that increase patient morbidity and risk for mortality, especially in the aging population. Effective prevention of SRRT may lead to more patients being eligible for a potential cure through HDT and stem cell transplantation.

About SRRT Consequences of Diffuse Injury to the Organ Vascular NichesThe human body is capable of renewing, healing and restoring organs.For example, the human oral-GI tract renews its lining every 3 to 7 days. Both the organ renewal and healing processes are dependent on organ stem cell vascular niches made up of stem cells, endothelial cells (cells that line blood vessels) and supportive cells.When tissues are injured, the vascular niche endothelial cells direct the stem cells, via angiocrine factor expression, to repair and restore the damaged tissue. This restorative capacity is most active during childhood and youth but starts to diminish with increasing age.HDT provided to eradicate cancer cells also cause diffuse, collateral damage to vascular niches of multiple healthy organs. In particular, the organs with the highest cell turnover (ones with most active vascular niches) are severely affected.Specifically, the oral-GI tract, dependent on constant renewal of its mucosal lining, starts to break down upon vascular niche injury.The mucosal breakdown can cause severe nausea, vomiting and diarrhea. In addition, the bacteria in the gut may escape into the circulation, resulting in patients becoming ill with endotoxemia, bacteremia or potentially lethal sepsis.HDT-related vascular niche damage can also occur in other organs resulting in severe or life-threatening complications involving the lung, heart, kidney, or the liver.Collectively, these complications are known as severe regimen-related toxicities or SRRT.SRRT can occur as frequently as 50% in lymphoma HDT-AHCT patients, with increased rate and severity in older patients.

About AB205AB-205 is a first-in-class engineered cell therapy consisting of proprietary 'universal' E-CEL (human engineered cord endothelial) cells.The AB-205 cells are intravenously administered after the completion of HDT on the same day as when the patient's own (autologous) blood stem cells are infused. AB-205 acts promptly to repair injured vascular niches of organs damaged by HDT.By repairing the vascular niches, AB-205 restores the natural process of tissue renewal, vital for organs such as oral-GI tract and the bone marrow. Successful and prompt organ restoration can prevent or reduce SRRT, an outcome that is beneficial to quality of life and cost reductive to the healthcare system.

About CIRMThe California Institute for Regenerative Medicine (CIRM) was established in November, 2004 with the passage of Proposition 71, the California Stem Cell Research and Cures Act. The statewide ballot measure provided $3 billion in funding for California universities and research institutions.With over 300 active stem cell programs in their portfolio, CIRM is the world's largest institution dedicated to stem cell research. For more information, visit http://www.cirm.ca.gov.

About Angiocrine Bioscience Inc.Angiocrine Bioscience is a clinical-stage biotechnology company developing a new and unique approach to treating serious medical conditions associated with the loss of the natural healing and regenerative capacity of the body.Based on its novel and proprietary E-CEL platform, Angiocrine is developing multiple therapies to address unmet medical needs in hematologic, musculoskeletal, gastrointestinal, soft-tissue, and degenerative/aging-related diseases.A Phase 3 registration trial is being planned for the intravenous formulation of AB-205 for the prevention of severe complications in lymphoma patients undergoing curative HDT-AHCT.This AB-205 indication is covered by the Orphan Drug Designation recently granted by the US FDA.In addition, Angiocrine is conducting clinical trials of local AB-205 injections for the treatment of: (1) rotator cuff tear in conjunction with arthroscopic repair; and, (2) non-healing perianal fistulas in post-radiation cancer patients.

For additional information, please contact:

Angiocrine Bioscience, Inc.John R. Jaskowiak(877) 784-8496[emailprotected]

SOURCE Angiocrine Bioscience, Inc.

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Findings could aid anti-tumor drug development

Researchers at Washington University School of Medicine in St. Louis and their colleagues at Imperial College London have identified how a key protein in cancer cells changes shape to kick-start the repair of DNA damage caused by chemotherapy or radiation. Blocking this built-in repair mechanism with a drug has the potential to make chemotherapy or radiation more effective, the researchers say. The key protein is called Mec1 in yeast and ATR in humans. The video shows two Mec1 molecules bound together (one is in color on the left; the other is grey on the right). The side in color shows how the protein moves to switch between active and inactive states.

Radiation and chemotherapy are designed to kill cancer cells. But for many patients, cancer cells can survive even after being hit with high doses of chemotherapy or radiation. To make treatment more effective, scientists are focusing on ways to tweak the inner machinery of cancer cells to make them more susceptible to dying.

A team at Washington University School of Medicine in St. Louis is making headway in such efforts. The researchers have identified how a key protein in cancer cells changes shape to kick-start the repair of DNA damage caused by chemotherapy or radiation. Blocking this built-in repair mechanism with a drug has the potential to make chemotherapy or radiation more effective, according to the scientists.

The study appears Nov. 9 in the journal Nature Structural & Molecular Biology.

Because this protein is essentially the same in lower organisms as well as people, the researchers studied the version of the protein found in yeast, called Mec1. Mec1 and its human counterpart, ATR, are activated when cells are stressed. The proteins are responsible for sensing and repairing DNA damage before cells replicate to prevent that damage from being passed down to daughter cells. In some cases, this activation is good, protecting healthy cells from DNA damage that could lead to cancer. But in other cases, such as cancer therapy, doctors would like to turn these repair mechanisms off so the cancer cells are more susceptible to death by further DNA damage. In this way, cancer cells hit with radiation and chemotherapy can be destroyed more easily.

Determining the structures of both the inactive and active forms of this protein gives new insights into how that transition takes place, not just for Mec1 and ATR but for other members of the same family of proteins, said senior author Peter M. Burgers, PhD, the M. A. Brennecke Professor of Biological Chemistry. ATR inhibition is a promising anti-cancer treatment when combined with radiation or chemotherapy. A handful of ATR kinase inhibitors exists, and one called ceralasertib is being tested in phase 2 clinical trials in the U.S. Our study provides a tool for improving current ATR kinase inhibitors or designing new ones in a laboratory. Providing high-resolution structures is a critical step in the intelligent design of selective inhibitors.

To determine these structures, the Burgers lab studied yeast with various mutations in this key protein and found one mutant that forced the protein into a permanent on position. With collaborators at Imperial College London, Luke Yates, PhD and Xiaodong Zhang, PhD, the researchers then determined the structure of the protein when constantly on, at an extremely high resolution on the scale of individual atoms.

We already knew what it looks like when its off, said first author Elias A. Tannous, PhD, a senior scientist in the Burgers lab. But there was a lot of speculation about what it looks like when its turned on. How does it change its shape? Does it break in two? Does it bind to something else? We didnt know. And it was interesting to find that it changes shape like a butterfly opening its wings.

These types of proteins control many aspects of the cell, from growth and viability to replication and response to stress, Tannous said. Its the master machinery of DNA damage response responsible for accurate DNA replication. If there is any error, it tells the cell to stop. This can be good or bad depending on the situation. In future research, we can use this knowledge of the structure to learn how to fine tune the activity of this type of protein, with the goal of using this information to design more effective cancer therapies.

This work was supported in part by the Wellcome Trust and the National Institutes of Health (NIH), grant number GM118129.

Tannous EA, Yates LA, Zhang X, Burgers PM. Mechanism of auto-inhibition and activation of Mec1-ATR checkpoint kinase. Nature Structural & Molecular Biology. Nov. 9, 2020. DOI 10.1038/s41594-020-00522-0

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Patients with multiple myeloma (MM) can safely undergo radiation therapy without disrupting their plan to receive chimeric antigen receptor (CAR) T-cell therapy, according to new research. The study, presented last month at the American Society for Radiation Oncologys annual meeting, was conducted online due to the coronavirus disease 2019 pandemic.

CAR T-cell therapy has increasingly been seen as a potential breakthrough treatment for patients with MM, as well as other types of cancers. The therapy involves reprogramming patients own immune cells before infusing them back into the patients, where they find and kill cancer cells.

The new study focuses on CAR T B-cell maturation antigen (CART-BCMA) treatment, which was developed at the University of Pennsylvania.

Shwetha Manjunath, MD, the studys lead author and a resident in radiation oncology at Penns Perelman School of Medicine, said in a press release that although radiation has long been used to help alleviate bone pain associated with relapsed or refractory MM, it was not known whether the therapy could be safely and effectively used in patients who would eventually go on to undergo CAR T-cell therapy.

To study this question, Manjunath and colleagues retrospectively identified 25 patients who received CART-BCMA therapy. Those patients were categorized into one of 3 groups:

The first group consisted of 4 patients. None of these patients experienced severe adverse effects like cytokine release syndrome (CRS) or grade 3 or higher gastrointestinal, infectious, liver-related, or neurological toxicities. Those patients also had lower rates of grade 4 hematologic toxicities, the authors said.

Among the 8 patients who had previous radiation, 3 experienced grade 3 or higher CRS. The remaining 13 patients, none of whom had undergone radiation in the year prior to CAR T-cell infusion, had 5 cases of grade 3 or higher CRS.

The authors found no decrease in overall survival or progression-free survival among the patients who underwent radiation.

The most important takeaway here is that bridging radiation doesnt appear to increase the risk of CRS or neurotoxicity, said Manjunath, in a press release. These patients safely received bridge radiation without it affecting the efficacy of CAR T cells or the rates of toxicity.

In fact, Manjunath said it may well be that radiation therapy actually helps the efficacy of CAR T-cell therapy.

Our work is hypothesis generating, hinting at a potential synergism between radiation and CART-BCMA therapy, which has been reported by others in the literature, she said, adding that future prospective trials of radiation and CART-BCMA are warranted to better understand the safety profile and long-term efficacy of the combination.

Reference

Manjunath SH, Cohen AD, Arscott WT, Maity A, Plastaras JP, Paydar I. Is bridging radiation (RT) safe in B cell maturation antigen-targeting chimeric antigen receptor T cells (CART-BCMA) therapy? Int J Radiat Oncol Biol Phys. 2020;108(suppl 3):S165-S166. doi:10.1016/j.ijrobp.2020.07.934

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Radiation Does Not Disrupt CAR T-Cell Therapy in Patients With MM, Study Finds - AJMC.com Managed Markets Network