Monthly Archives: August 2021

The addition of zanubrutinib to the guidelines was based on the findings from the ASPEN studypublished in Blood. The study compared the safety and efficacy of zanubrutinib, a novel highly selective Bruton tyrosine kinase (BTK) inhibitor, with ibrutinib, a first-generation BTK inhibitor.2

In ASPEN, 28% of patients on zanubrutinib and 19% on ibrutinib achieved a very good partialresponse (VGPR); no patient achieved a complete response (CR). The study did not meet the primary end point, which was proportion of patients achieving CR or VGPR, but the investigators noted that there was a trend toward better disease control for zanubrutinib vs ibrutinib.

Major response rate was similar (77% for zanubrutinib vs 78% for ibrutinib), as was progression-freesurvival (85% for zanubrutinib vs 84% for ibrutinib). Patients on zanubrutinib had fewer instancesof atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, andpneumonia, as well as adverse events that led to treatment discontinuation.

This study established that zanubrutinib is highly effective in the treatment of WM; zanubrutinibis associated with important safety advantages, especially with respect to cardiovascular toxicity,the authors wrote.

The data from ASPEN was used in a supplemental new drug application (sNDA) with the FDA forzanubrutinib in the treatment of WM, which was submitted in February 2021. Health Canada approved zanubrutinib in WM in March based on the findings of ASPEN.

We are pleased that the FDA has accepted the sNDA for Brukinsa in WM, a rare disease with significant morbidity, Jane Huang, MD, chief medical officer, Hematology, BeiGene, said in a statement. BTK inhibitors have transformed the treatment of WM in recent years, but discrepancies in response exist in patients with different subtypes, and toxicity can remain an issue.3

References1. NCCN. Clinical Practice Guidelines in Oncology. Version 1.2022. Waldenstrm macroglobulinemia/lymphoplasmacytic lymphoma. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=14752. 2. Tam CS, OPat S, DSa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenstrm macroglobulinemia: the ASPEN study.Blood. 2020;136:2038-2050. doi:10.1182/blood.20200068443. BeiGene announces US FDA acceptance of supplemental New Drug Application for Brukinsa (zanubrutinib) in Waldenstrms Macroglobulinemia. News release. BeiGene. Published February 17,2021. Accessed July 20, 2021. https://ir.beigene.com/news-releases/news-release-details/beigene-announces-us-fda-acceptancesupplemental-new-drug

With more treatment options needed in glioblastoma multiforme (GBM) to successfully attack disease, attention has been paid to chimeric antigen receptor (CAR) T-cell therapy, which hasshown great promise in hematologic malignancies and is being studied in other settings, includingcentral nervous system solid tumors, like GBM. In a recent paper, investigators provide a look atclinical trials currently assessing the potential of treatment for the disease.

Although theres hope that CAR T-cell therapy can revolutionize the way GBM is treated, there isstill more research to be done, investigators write inCancer Medicine, noting that research on CART-cell therapy in this setting is still in early stages.1

Despite the promising results of CAR T technology in hematological malignancies, CAR T cellsfor GBM are still in their earlier stage, wrote the investigators. Several GBM-associated antigenshave served as the targets of ongoing clinical trials (EGFRvIII, NKG2D, B7-H3, CD147, IL13Ralpha2,and HER2). Most of the current clinical trials are still in phase 1, testing the safety and efficacy ofmostly second-generation CAR T cells constructed with CD28 and 4-1BB costimulatory intracellulardomains.

The investigators write that, to date, evidence suggests combined therapy is more effective thanmonotherapy in GBM, which not only gives insight into how to enhance the efficacy of CAR T-celltherapy but also to potentially curtail adverse effects. The investigators outlined various ongoingtrials of CAR T-cell therapy that combine the therapy with other agents in patients with GBM.

With 70% of patients with GBM expressing B7-H3, which is not expressed on normal tissues, 1 ongoing trial is currently assessing the safety and tolerability of B7-H3 CAR T-cell therapy withtemozolomide, with B7-H3 CAR T being injected between temozolomide cycles. Data from the study are expected in 2022.2

EGFRvIII CAR T-cell therapy is being studied in several trials, with an ongoing phase 1 studyassessing the therapy in combination with temozolomide and another assessing EGFRvIIICAR T following radiosurgery in patients with recurrent GBM.

CAR T-cell therapy in combination with immune checkpoint inhibitors is also being assessed for both recurrent and resistant disease, say the investigators. A phase 1 trial is currently looking at the safety and efficacy of IL13Ralpha2-CRT T cells used alone or in combination with nivolumab and ipilimumab.

Although still in the preclinical stage, Fc-CRs T cells may prove to be a leader in the treatment ofGBM and other solid tumors, say the investigators. As research on CAR T-cell therapy in GBMprogresses, the investigators are also calling attention to the challenges facing the therapy inthe disease, including the highly unstable tumor microenvironment and the variable genetic natureof the disease.

The mechanism by which the apparent tumor responses or growth delay in CAR-T cell-treatedGBM are multifactorial. This cannot be attributed to the therapy but could instead result from differences in the natural history of disease between patients, commented the investigators. Although there are no direct ways to demonstrate the actual killing of tumor cells by CAR T in situ, previous clinical and preclinical data suggest that CAR-T-EGFRvIII cells induce their action by antigen-directed cytolysis after crossing the bloodbrain barrier.

References

1. Marei HE, Althani A, Afifi N, et al. Current progress in chimeric antigen receptor T cell therapy for glioblastoma multiforme.Cancer Med. Published online June 19, 2021. doi:10.1002/cam4.4064

2. Pilot Study of B7-H3 CAR-T in Treating Patients With Recurrent and Refractory Glioblastoma. Updated May 12, 2020. Accessed July 15, 2021. https://clinicaltrials.gov/ct2/show/NCT04385173.

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August 2021: Targeted Therapy & Immuno-Oncology - AJMC.com Managed Markets Network

Too many exhausted T cells left in the wake of aggressive chemotherapy regimens for patients with advanced chronic lymphocytic leukemia (CLL) make it more challenging for chimeric antigen receptor (CAR) T cell therapy to do its job. Now, a new study from researchers in the Perelman School of Medicine at the University of Pennsylvania shows how to overcome this type of resistance and reinvigorate these T cells with an experimental small molecule inhibitor.

Reporting online in the Journal of Clinical Investigation, the team shows how the drug, known as JQ1, improved CAR T cell function by inhibiting what is known as the bromodomain and extra terminal (BET) proteins. BET, the researchers showed, can disrupt CAR expression and key acetylated histone functions in T cells in CLL.

The findings demonstrate, for the first time, this mechanism of resistance and present a much-needed target for CLL when treating patients with cellular therapies like CAR. Only a small subset of patients with advanced CLL respond to CAR T cell therapycompared to 80 percent of acute lymphocytic leukemia patients with advanced disease.

Why CAR T cells fail to fully attack cancer cells in so many CLL patients is an important question that needs to be answered in order to expand the use of these immunotherapies in CLL and other cancers, said senior author Joseph A. Fraietta, PhD, an assistant professor of Microbiology at Penn, and member of the Center for Cellular Immunotherapies. Treating these war weary T cells during the CAR T cell engineering process has the potential to boost responses, weve shown here. Its setting the stage for a very promising set of next steps that rationalize further studies, including clinical trials, to prove this approach is safe and feasible.

Using the small molecule inhibitor and the T cells and CD19 CAR T cells from multiple previously treated patients, the researchers demonstrated that the BET protein plays a role in downregulating CAR expression, and that, if blocked, can diminish CAR cell T cell exhaustion and increase the production of CAR T cells from CLL patients with poor lymphocytes.

Treatment with JQ1 also increased levels of various immunoregulatory cytokines and chemokines previously reported to be produced by CAR T cells in CLL during successful therapy. The array of native immune and CAR cells mirrored those found more typically in patients who do respond.

Given this observed reinvigoration of dysfunctional CLL patient CAR T cells by BET inhibition, the authors suggest that incorporating JQ1 into cellular engineering and expansion processes could lead to a generation of less defective and more potent final CAR T cells for patients.

To what extent the above pathways contribute to the effects of JQ1 on CAR T cells is a focus of ongoing investigations for the research group.

This work shows us that T cells can be taught new tricks, said Bruce Levine, PhD, the Barbara and Edward Netter Professor in Cancer Gene Therapy in Penns Perelman School of Medicine, and co-author on the study. That is to say that the methods of manufacturing can be adapted to improve CAR T cell function, so that what would have been exhausted or dysfunctional cells can now be reinvigorated, and potentially lead to better clinical responses in more patients than before.

Reference:Kong W, Dimitri A, Wang W, et al. BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia. J Clin Invest. 2021;131(16). doi:10.1172/JCI145459

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

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Investigational Inhibitor Improves Responses to Cellular Therapies in Advanced Leukemias - Technology Networks

WASHINGTON, Aug. 16, 2021 /PRNewswire/ --The ASH Research Collaborative (ASH RC) has announced the first 10 clinical research consortia to join the ASH RC Sickle Cell Disease Clinical Trials Network. The sites will be able to enroll children and adults living with sickle cell disease (SCD) within their patient populations in clinical trials as part of an unprecedented national effort to streamline operations and facilitate data sharing to expedite the development of new treatments for this disease.

SCD is a chronic, progressive, life-threatening, inherited blood disorder that affects more than 100,000 Americans and an estimated 100 million persons worldwide. Clinical trials hold incredible promise for the development of much-needed new treatments, and possibly even a cure. While there are currently only four U.S. Food and Drug Administration (FDA)-approved drugs to treat the disease, there is a robust SCD drug development pipeline that will drive demand for clinical trials to a new level, providing a prime opportunity to advance treatment and care of those affected by SCD.

The SCD Clinical Trials Network is poised to accelerate progress by bringing together a community of research-ready clinical sites and experienced investigators, connecting industry sponsors to sites and the community, leveraging real world data to support clinical trials through the ASH RC Data Hub, and facilitating efficient, coordinated clinical trial startup. Engagement with the community has been foundational to the development of the SCD Clinical Trials Network. The ASH RC provides support for SCD Community Advisory Boards at each consortium to ensure that Network efforts are informed by the needs and desires of those living with and caring for those with SCD at both local and national levels.

"We're entering a new era for how clinical trials are designed and conducted, and the ASH Research Collaborative SCD Clinical Trials Network is committed to ensuring that the voice of the SCD community is heard at every stage of the process, while ensuring a coordinated, efficient approach. We hope to accelerate our ability to bring new treatments to individuals who are living with this difficult disease," said Martin S. Tallman, MD, of Memorial Sloan Kettering Cancer Center, who serves as president of the ASH Research Collaborative and the American Society of Hematology.

Each consortium in the Network consists of a clinical trials unit (CTU) that serves as the lead clinical trial site, or hub, providing administrative expertise and infrastructure to support various clinical research sites (CRS), or spokes, within each consortium (see full list below). A CRS can be a hospital, outpatient clinic, community health center, private practice, or local health department clinic. Approximately 24,000 children and adults living with sickle cell disease are currently represented by the Network.

"The ASH RC Sickle Cell Disease Clinical Trials Network is uniquely situated to accelerate clinical research and the development of novel therapeutics to help those living with sickle cell disease," said Charles S. Abrams, MD, Chair of the ASH RC SCD Clinical Trials Network Oversight Committee. "This an unprecedented opportunity to make a profound difference in the lives of people with sickle cell disease. We are committed to partnering with patients, families, and the broader sickle cell disease community."

Inclusiveness, commitment to rigorous standards, and improving the access of the SCD community to clinical trials are guidingprinciples of the SCD Clinical Trials Network. In addition to the ten consortia that have already been activated, additional network sites are in the onboarding process. Additions to the SCD Network will continue to be announced on a rolling basis.

The ASH RC Sickle Cell Disease Clinical Trials Network Sites:

Central Carolinas Clinical Trials CollaborationClinical Trials Unit: Duke University Medical Center (Adult & Pediatrics)Clinical Research Sites: UNC Medical Center (Adult & Pediatrics; Wake Forest Baptist Health (Adult & Pediatrics)

Chicagoland Regional Research in Sickle Cell Partnership (CRiSP) Clinical Trials Unit: Ann & Robert H. Lurie Children's Hospital of Chicago Clinical Research Sites:Indiana Hemostasis and Thrombosis Center; Northwestern Memorial Hospital; OSF Healthcare Children's Hospital of Illinois; University of Illinois at Chicago; University of Chicago (University Hospital; Comer Children's Hospital; LaRabida Children's Hospital)

DMV Sickle Cell Disease Consortium (DMVSCDC) Clinical Trials Unit: Children's National Health SystemClinical Research Sites:Howard University; Kaiser Permanente Mid-Atlantic Permanente Medical Group (MAPMG) and Mid Atlantic Permanente Research Institute (MAPRI); Medstar Washington Hospital Center; Pediatric Specialists of Virginia; Virginia Commonwealth University/Children's Hospital of Richmond

The Heartland/Southwest SCD Consortium Clinical Trials Unit: Washington University School of Medicine Clinical Research Sites:Children's Mercy of Kansas City; University of Arkansas for Medical Sciences; University of Iowa Medical Center; University of Missouri Health Center; University of Oklahoma Health Sciences Center

New York Sickle Cell CTN Consortium Clinical Trials Unit: Montefiore Medical Center Clinical Research Sites:Brookdale Hospital Medical Center; Columbia University Medical Center; Cohen Children's Medical Center; Cornell Medical Center; Interfaith Medical Center; Methodist Hospital; Mount Sinai Hospital

North Texas Clinical Trials Consortium Clinical Trials Unit: UT Southwestern Medical Center Clinical Research Sites:Children's Medical Center Dallas; Clements University Hospital; Cook Children's Health Care System; Medical City Children's Hospital, Dallas; Parkland Health and Hospital System

SCD Clinical and Research Consortium of Southeastern WisconsinClinical Trials Unit:Medical College of WisconsinClinical Research Sites: Children's Hospital of Wisconsin; Froedtert Hospital

Sickle Mid Atlantic Research Team (SMART) Clinical Trials Unit: The Johns Hopkins University School of MedicineClinical Research Sites:Charleston Area Medical Center (CAMC); Christiana Care Health Services; Herman & Walter Samuelson Children's Hospital at Sinai Hospital; Inova Health System (Fairfax); Johns Hopkins All Children's Hospital- FL; Nemours / Alfred I DuPont Hospital for Children; Peninsula Regional Medical Center; University of Maryland Medical Center

South Carolina Sickle Cell Disease Network Clinical Trials Unit: Prisma Health Children's Hospital - UpstateClinical Research Sites:Medical University of South Carolina Lifespan Comprehensive SCD Center; Prisma Health Children's Hospital - Midlands

Western States Sickle Cell Disease Clinical Trials Network (WeSt SCD CTN) Clinical Trials Unit: University of California San Francisco Benioff Children's Hospital of Oakland Clinical Research Sites:UCSF Helen Diller Medical Center at Parnassus; UCSF Zuckerberg San Francisco General Hospital; University of California Davis Medical Center

More Information:

About the ASH Research CollaborativeThe ASH Research Collaborative (ASH RC) is a non-profit organization established by the American Society of Hematology (ASH)to improve the lives of people affected by blood diseases by fostering collaborative partnerships to accelerate progress in hematology. The foundation of the ASH RC is its Data Hub and Clinical Trials Network. TheData Hub, a technology platform that facilitates the exchange of information by aggregating and sharing research-grade data on hematologic diseases. The Sickle Cell Disease Clinical Trials Network (CTN) optimizesthe conduct of clinical trials research in sickle cell disease (SCD) and leverages the Data Hub to collect key information and identify gaps to advance SCD research and treatment.

SOURCE American Society of Hematology

http://www.hematology.org

Link:
ASH Research Collaborative Announces First Ten Clinical Trial Consortia to Join the Sickle Cell Disease Clinical Trials Network - PRNewswire

reproduction

Living for many years with quality of life, with health, without disease, is the dream of any human being. As far as science and technological progress depend, this is the near future. The trend is global and Brazil can be proud to be at the forefront of this movement.

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In this scientific field, the highlight is the research on the use of mesenchymal stem cells, which function in the regeneration of many tissues of the human body, and the release of chemicals that facilitate the regeneration process and that modulate the immune system. These cells are multipotent, as they have the potential to form different tissues.

Mesenchymal stem cells, especially those taken from baby teeth, have a high quality because they are so small. They have the ability to help regenerate different types of tissues and organs, such as: skin, pancreas, cartilage, nervous tissue, fatty tissue, bone, heart tissue, liver, teeth, eyes, and muscles. In addition, the improvement in the quality of life or even the treatment of chronic diseases or diseases that are now considered incurable such as Parkinsons disease, the consequences of stroke and even spinal cord injuries are getting closer.

With this important discovery, people will be able to live longer and better, using their own materials to regenerate any type of tissue, eliminating the risk of rejection. Currently, for example, we are having tremendous success in the experimental treatment of children with a cleft lip, which is conventionally corrected with highly invasive surgery, which occurs around 8 years of age and consists in removing part of the hip bone to bridge the gap, an extremely painful procedure with slow recovery. On average, up to three surgeries are needed. With stem cell therapy, bone tissue is formed, and within six months, the cleft lip and palate are completely closed. This is just an example of what is happening and what lies ahead. More effective, less painful treatments and better results are becoming a reality, says scientist Jose Ricardo Muniz Ferreira, who has studied and improved the technology of extracting cells from baby teeth, storing them and implanting them. A true treasure: young, highly versatile stem cells, he asserts.

Ferreira is the president of R-Crio a Brazilian cell treatment center with stakeholders from various fields such as: dentistry, biology, biomedicine, medicine and engineering which, despite the unstable economic scenario that our country is going through, decided to invest heavily because they know the benefits that can That this area brings to all residents. According to him, Brazil is far ahead in this issue compared to other countries. In our travels to universities around the world, such as England and India, where I have spoken recently, I have spoken a lot with many colleagues and have been able to see Brazil at the forefront in this sector, he celebrates. He also says that patent production by Brazilian researchers is increasing in this sector, making our country a reference in this matter. We are no longer the stigmatized country of selling goods and we are increasingly moving towards the production of intellectual property, the generation of business and jobs and the promotion of the economy and health, he explains.

According to the scientist, public health in our country tends to gain a lot from regenerative medicine. In addition to the population health gain, the government will save significantly by using it.

Recently, the National Health Surveillance Agency ANVISA, through Resolution 214 and Public Consultation 416, is working in favor of regulating good research practices in this area, strengthening work with stem cells.

It is up to the press and the community to spread this good news! It has been and will remain increasingly constant and important in peoples lives, increasing expectations and quality of life, concludes scientist Jos Ricardo Muniz Ferreira.CLICK HERE AND GET NEWS IN OUR WHATSAPP AND TELEGRAM GROUPS

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Medical developments in the near future - BOB fm

From left Evanthia Roussos Torres, Elizabeth Jaffee, Roisin Connolly and Vered StearnsImage Courtesy of Johns Hopkins Kimmel Cancer Center

Mega Doctor NEWS

byJohns Hopkins Medicine

Newswise Combining a histone deacetylase inhibitor drug with immunotherapy agents is safe, and may benefit some patients with advanced cancers that have not responded to traditional therapy, according to results of a phase 1 clinical trial led by researchers at theJohns Hopkins Kimmel Cancer Center,Bloomberg~Kimmel Institute for Cancer Immunotherapyand several other centers including University of Pittsburgh Cancer Institute, Yale Cancer Center and City of Hope in Los Angeles, which participated in study enrollment, and the University of Southern California and University College Cork in Ireland, which collaborated on analysis of the data.

During the study, 33 patients with advanced solid tumors received the histone deacetylase inhibitor drug entinostat for two weeks. Then, some patients received the immunotherapy agent nivolumab, a checkpoint inhibitor, in combination with the entinostat, while others received both nivolumab and a second checkpoint inhibitor agent, ipilimumab, after the initial dosing with entinostat.

Checkpoint inhibitors, such as nivolumab and ipilimumab, release important brakes that permit the immune system to fight the cancer cells. The epigenetic inhibitor drug entinostat has been shown in preclinical models and laboratory studies (which led to this current clinical trial) to drive changes in the chemical environment of cells to make them more amenable to immunotherapy, saysVered Stearns, M.D., director of the Womens Malignancies Disease Group at the Johns Hopkins Kimmel Cancer Center.

The authors found that the objective response rate, or percentage of patients whose cancer responded to therapy, was 16%. One patient with triple-negative breast cancer had a complete response, meaning a total shrinkage of the cancer. Because the cancer types included in the study are not felt to have high response rates to immune checkpoint therapy, these preliminary results are very promising. Treatment-related adverse events were mostly low grade, and included fatigue, nausea, anemia and diarrhea.

These results were published online in the June 16 issue ofClinical Cancer Research.

Study co-author Evanthia T. Roussos Torres, M.D., Ph.D., an adjunct professor at Johns Hopkins and assistant professor at the University of Southern Californias Keck School of Medicine and oncologist and researcher with USCs Norris Comprehensive Cancer Center in Los Angeles, says the entinostat functioned as an immune system-priming agent prior to using immunotherapy in solid tumors that traditionally are nonresponsive to checkpoint inhibition therapy.

One of the major findings of our study is that this is a safe and tolerable combination of therapies, she says. There arent very many trials investigating dual immune checkpoint inhibition in combination with other novel therapeutics. We determined a safe, tolerable dose with this combination that had very few adverse effects. That is significant.

The researchers collected blood and tumor samples from the 33 patients before and after the two weeks of entinostat to assess the impact of the entinostat on the immune system, and also after the addition of the immune checkpoint agents to evaluate the effect of each of the treatments on the immune environment. The study team found a significant increase in the ratio of CD8/FoxP3 gene expression in tumors following checkpoint inhibitor treatment but not after entinostat treatment alone. This suggests that the combination therapy helped increase both cytotoxic immune system T cells immune cells that directly kill cancer cell as well as decrease immune system T regulatory cells immune cells that modulate the immune response which equaled a stronger immune response, Roussos Torres says.

The median age of participants was 60, most (91%) were female, 30% had breast cancer (the main tumor type studied) and the median number of prior regimens tried for their disease was 3.5. The median progression-free survival, or time until disease progression or death, was 6.1 months, and median overall survival was 10.6 months. Stable disease, considered the best response, was observed in 44% of participants. Clinical benefit rate, or the percentage of patients who achieved stable disease, or partial or complete response, was 60%.

The most robust increases in CD8/FoxP3 ratio were observed in two patients with HR-positive breast cancer who experienced a partial response and stable disease. Three additional patients who experienced stable disease had adenocarcinoma, a cancer of glandular tissue.

The complete response in a patient with breast cancer is a promise that there may be a role for this combination of therapies in breast cancers, says senior study author Roisin M. Connolly, M.B.B.Ch., M.D., an adjunct professor at Johns Hopkins and chair in cancer research at University College Cork and Cork University Hospital in Ireland. Immunotherapy hasnt been as big a blockbuster to date in advanced breast cancer as in other cancers, such as lung cancers or melanoma. This study paves the way for novel combination therapies that have the potential to improve response rates to immune checkpoint inhibitors in traditionally less-responsive tumor types.

This drug combination is being investigated further in a group of 24 patients with HER2-negative breast cancer as part of the same NCI-sponsored clinical trial. We are excited to have completed accrual to these ongoing studies in advanced HER2-negative breast cancer, and expect to report on these findings later this year, says Stearns.

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Inhibitor Drug Entinostat Primes the Body to Better Respond to Anti-Cancer Treatment with Immunotherapy - Mega Doctor News