Fill out your #OncMadness 2020 bracket here. And learn more.
CAR-T in Hematologic Cancers
Targeting cancer via immunomodulation has been the holy grail of oncology. Over the last few years, the hottest topic in hematology has been chimeric antigen receptor (CAR) T-cell therapy, or CAR-T.
To discuss the development of CAR T-cell therapy, one must look back at the fascinating history of Carl June, MD. In the 1980s, when so many Americans were partying like it was 1999, June began his journey to become an oncologist. Researchers had learned that in patients with an identical twin, leukemia could be cured via high-dose chemotherapy followed by a bone marrow transplant. But most patients didn't have a twin, so hematologists had to identify a best match. Given their different immune systems, patients began experiencing graft-versus-host disease.
June began working on a way to achieve the same benefits of a transplant, without the transplant. His approach, using patients' own immune systems, took much teamwork and about 30 years to develop.
To hear June share his memories is fascinating. Given that he was in the Navy, he learned about radiation-induced bone marrow failure from victims of Chernobyl. The Navy wanted to learn how to replenish immune systems post-radiation exposure, so he set about doing this.
As geopolitical pressures changed and the likelihood of nuclear war decreased, June and his team shifted their focus to rebuilding T-cell populations in patients with HIV and AIDS. They harvested T cells from patients, amplified them, and infused them back into patients. He recalls being shocked that it worked!
In 1999, June joined the faculty of the University of Pennsylvania and resumed studying leukemia, now applying his work in HIV to the care of cancer patients. The first cancer patient was treated with CAR T-cell therapy in 2010 and the treatment ultimately led to the 2017 FDA approval of tisagenlecleucel (Kymriah) for pediatric acute lymphoblastic leukemia (ALL). A year later tisagenlecleucel gained approval for adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Adverse events associated with this therapy are significant and include cytokine release syndrome (CRS) and neurologic toxicity.
CRS occurs after infusion and may include high fever, hypotension, and other serious hemodynamic changes. Fever occurs as tumor cells are being killed, and larger tumor volumes can yield higher fevers. CRS can be managed with agents that block the effects of interleukin-6, like tocilizumab (Actemra), and/or corticosteroids.
Neurotoxicity from CAR-T is now described as immune effector cell-associated neurotoxicity syndrome, and is characterized by global encephalopathy, aphasia, seizures or seizure-like activity, obtundation, tremor, myoclonus, and hallucinations. It is almost always reversible.
In addition to tisagenlecleucel, another CAR T-cell product, axicabtagene ciloleucel (Yescarta) is approved for certain types of non-Hodgkin's lymphoma. These therapies can only be administered by authorized clinicians.
If patients are considered to be candidates for CAR T-cell therapy, they have T cells harvested via leukapheresis. They undergo engineering so that they express CARs on their surface, then are multiplied. This process is estimated to take 8 to 12 days. When ready, they are infused back into the individual. Some patients will have cytoreductive chemotherapy prior to infusion. After infusion, patients remain in the hospital for close monitoring. The first month is critical in the process of recovery. Once injected into the patient, the CAR T cells expand from 1,000- to more than 10,000-fold. This expansion peaks at 10 to 14 days and coincides with the onset of CRS.
Results from ELIANA, a phase II trial of tisagenlecleucel in pediatric and young adult patients with CD19-positive relapsed or refractory B-cell ALL, demonstrated an overall remission rate of 81% at 3 months. Moreover, rates of event-free survival and overall survival (OS) were 73% and 90%, respectively, at 6 months and 50% and 76% at 1 year. CRS occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care. Long-term follow-up from the trial showed that two-thirds of those who attained complete responses remained in remission at 18 months.
In the JULIET trial, tisagenlecleucel was given to adult patients with relapsed or refractory DLBCL who were ineligible for or had disease progression after autologous stem cell transplant. Infusions were given to 93 patients and the therapy yielded an overall response rate of 52%, with complete responses in 40% and partial responses in 12%. At 12 months after initial response, the rate of relapse-free survival was 65%, and nearly 80% in those who achieved a complete response. The most common grade 3/4 adverse events of special interest included CRS (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion.
In the ZUMA-1 trial, treatment with axicabtagene ciloleucel led to a response rate of 82% among 101 patients with refractory DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. In all, 54% had a complete response. With a median follow-up of 15.4 months, 42% of the patients had maintained their response, including 40% of complete responders. Half of the patients remained alive at 18 months. The most common adverse events of grade 3 or higher were neutropenia in 78%, anemia in 43%, and thrombocytopenia in 38%. Grade 3 or higher CRS and neurologic events occurred in 13% and 28%, respectively. Three patients died during treatment.
At the recent American Society of Hematology (ASH) annual meeting, data from the phase I LEGEND-2 trial was presented to much enthusiasm. LCAR-B38M, a newer CAR T-cell therapy, was given to 57 individuals with relapsed/refractory multiple myeloma, leading to a response rate of 88%, with complete responses in 74%. Median duration of response was 22 months, and the 18-month OS rate reached 68%.
There are multiple ongoing trials using the FDA-approved compounds in other settings. Additional therapies are under investigation, and next-generation "smarter" CAR-T products are being developed. Those that address multiple targets will be prioritized. Hopefully, manufacturing and production will also be streamlined.
'Off the Shelf' Cellular Therapy
Despite the excitement surrounding CAR-T therapies, there have been concerns as well. These are patient-specific, personalized therapies that require waiting periods while the product is created. With traditional CAR T-cell therapy, patients must be well enough for cell collection and remain clinically stable for approximately 1 month before cells can be made and re-infused. It is estimated that about one-third of patients enrolled in CAR-T trials never make it to infusion due to the severity of their illness. Patients must also have an adequate supply of T cells to start with.
The nature of this personalized therapy means that there is a lot of work involved, along with the potential for human error. Associated costs are also very high, with estimates for the currently available products ranging from $370,000 to just shy of $500,000. This excludes costs of administration and costs related to prolonged hospitalizations due to adverse events.
Given the challenges of CAR-T therapy, clinical investigators are working to create a next generation of cellular therapies known as "off-the-shelf" treatments that can originate via a healthy donor's cells, and then be mass-produced and used for multiple patients -- so-called universal CAR T cells.
Multiple collaborators have active open-label, single-arm phase I trials for an off-the-shelf allogeneic CAR-T product called UCART19.
At ASH 2018, pooled data on 21 patients treated with UCART19 in two phase I trials -- PALL and CALM -- were presented. Of 17 patients who also received fludarabine/cyclophosphamide and an anti-CD52 monoclonal antibody, 82% achieved complete remission. In four patients who only received UCART19 and fludarabine/cyclophosphamide, no responses were observed and there was minimal UCART19 expansion. Safety was encouraging, as only two cases of low-grade graft-versus-host disease were seen, and neurotoxicity and CRS were as expected and manageable.
More recently, data from a large phase I study presented at the ASH 2019 meeting showed that 46% of 191 patients with relapsed, difficult-to-treat non-Hodgkin's lymphoma responded to mosunetuzumab, an investigational bispecific antibody. This included patients who were resistant or refractory to approved CAR T-cell therapies. The new agent, which targets CD3 and CD20, induced objective responses in 37% of patients with aggressive lymphomas and in 63% of those with indolent forms of the disease. In a subgroup of 18 patients with prior CAR-T exposure, seven responded to mosunetuzumab.
Advantages of such "off-the-shelf" therapies include their increased availability, that they eliminate the need for patients to have leukapheresis and the waiting period involved, and they are likely to be less expensive in comparison to traditional CAR-T.
We will likely witness an explosion of these products over the next few years.
Now that you've reviewed this Scouting Report, make sure you catch all the #OncMadness 2020 Scouting Reports to make the best picks!
See the original post:
- Researchers find that fish oil may help with depression - Jill Lopez - July 16th, 2020
- How frogs became green again, and again, and again : Research Highlights - Nature.com - July 16th, 2020
- Pressing ahead - PharmaTimes - July 16th, 2020
- Citius Pharmaceuticals Brings on Myron S. Czuczman, MD as Chief Medical Officer (CMO) and Executive Vice President - PRNewswire - July 16th, 2020
- Global thirst for electricity is fuelling the rise of a potent greenhouse gas - Nature.com - July 6th, 2020
- Check it Out: Beat summer boredom by reading a book - The Columbian - July 6th, 2020
- Cell Separation Technology Market by Leading Manufacturers, Demand and Growth Overview 2019 to 2027 - Jewish Life News - July 4th, 2020
- Its not just the lungs COVID-19 can affect the brain and heart of those infected, researchers say - FOX 10 News Phoenix - July 1st, 2020
- Adult Stem Cells // Center for Stem Cells and Regenerative ... - July 1st, 2020
- Label-free sensing of exosomal MCT1 and CD147 for tracking metabolic reprogramming and malignant progression in glioma - Science Advances - June 30th, 2020
- Novel coronavirus infection might trigger type-1 diabetes - The Hindu - June 30th, 2020
- Recovering from Cancer, a Stem Cell Transplant and Coronavirus - Cancer Health Treatment News - June 30th, 2020
- FDA Approves Merck's KEYTRUDA (pembrolizumab) for the Treatment of Patients with Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma (cSCC) that... - June 30th, 2020
- Century Therapeutics Announces Acquisition of Empirica Therapeutics - Business Wire - June 30th, 2020
- Century Therapeutics Announces Acquisition of Empirica Therapeutics | DNA RNA and Cells | News Channels - PipelineReview.com - June 23rd, 2020
- BrainStorm Cell Therapeutics to Join the Russell 2000 Index and Russell 3000 Index - PRNewswire - June 23rd, 2020
- Acute Myeloid Leukemia (AML) Therapeutics Market Promising Growth Opportunities over 2017 2025 - 3rd Watch News - June 23rd, 2020
- UK Startup Bags 37M to Remove Cell Therapy Manufacturing... - Labiotech.eu - June 16th, 2020
- EHA25Virtual: Adult Patients With Sickle Cell Disease May Be at Increased Risk of Adverse Outcomes From COVID-19 - Yahoo Finance - June 16th, 2020
- CRISPR Therapeutics and Vertex Announce New Clinical Data for Investigational Gene-Editing Therapy CTX001 in Severe Hemoglobinopathies at the 25th... - June 16th, 2020
- BrainStorm to Present at the Raymond James Human Health Innovations Conference - PRNewswire - June 12th, 2020
- Mesenchymal Stem Cells Market - Advances & Applications scrutinized in the new analysis - WhaTech Technology and Markets News - June 12th, 2020
- Autolus Therapeutics presents AUTO1 and AUTO3 data at the 2020 EHA25 Virtual Congress - BioSpace - June 12th, 2020
- Genmab Announces European Marketing Authorization for the Subcutaneous Formulation of DARZALEX (daratumumab) for the Treatment of Patients with Multi... - June 12th, 2020
- Stem Cell Therapy Seen to Help COPD Patients with Severe Inflammation - COPD News Today - June 8th, 2020
- Stem Cells Market Analytical Overview, Growth Factors, Demand and Trends Forecast to 2028 - News Collective - June 8th, 2020
- Stem Cell Assay Market-Top Companies, Business Growth And Investment Opportunities, Share and Forecasts 2025 - Jewish Life News - June 8th, 2020
- Creating hairy human skin: Not as easy as you think - Science Codex - June 8th, 2020
- Global Stem Cells Market 2020 (COVID-19) Impact Analysis: Business Trends, Growth Insight, Statistics And Forecast to 2025 - Surfacing Magazine - June 8th, 2020
- Ide-cel Appears Active in Almost Three-Fourths of Heavily Pretreated Patients with Myeloma - Cancer Network - June 8th, 2020
- Study reveals birth defects caused by flame retardant - University of Georgia - June 8th, 2020
- Buckeye butterflies get their color from their scales - Massive Science - June 3rd, 2020
- Gracell Announces Two Presentations at the Annual Meeting of American Society of Clinical Oncology (ASCO) - PRNewswire - May 31st, 2020
- Stem cell treatments elicit full structural regeneration of the sun-aged skin - News-Medical.Net - May 29th, 2020
- AgeX Therapeutics and Sernova to Collaborate to Engineer Universal Locally Immune Protected Cell Therapies for Type I Diabetes and Hemophilia A -... - May 29th, 2020
- Genmab Announces Positive Topline Results in Phase III ANDROMEDA Study of Daratumumab in Light-chain (AL) Amyloidosis - Financialbuzz.com - May 29th, 2020
- Opdivo + Yervoy receive FDA approval combined with limited chemotherapy as first-line treatment of metastatic or recurrent NSCLC - The Cancer Letter - May 29th, 2020
- AUGUSTMAN Grooming Awards 2020 Part IV: Best Head-To-Toe Treatment Services For Gentlemen - AUGUSTMAN - May 29th, 2020
- Merck's KEYTRUDA (pembrolizumab) Superior to Standard of Care Chemotherapy in Patients with MSI-H Colorectal Cancer - BioSpace - May 29th, 2020
- KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) Combination Demonstrated Clinically Meaningful Tumor Response Rates in Unresectable Hepatocellular... - May 29th, 2020
- Canine Stem Cell Therapy Market Covid-19 Impact In 2026 | In-depth Analysis, Global Market Share, Top Trends, Professional & Technical Industry... - May 27th, 2020
- Looking toward the Future of Cell & Gene Therapies - Genetic Engineering & Biotechnology News - May 27th, 2020
- Past ISP Projects, School of Medcine - UC San Diego Health - May 27th, 2020
- Expression Therapeutics Announces IND Approval by the FDA for Hemophilia A Gene Therapy | DNA RNA and Cells | News Channels - PipelineReview.com - May 27th, 2020
- Immunotherapy Drug Market Global Trends, Market Share, Industry Size, Growth, Opportunities, and Market Forecast 2020 to 2025 - 3rd Watch News - May 27th, 2020
- Incyte and MorphoSys Announce the Validation of the European Marketing Authorization Application for Tafasitamab - Business Wire - May 21st, 2020
- Mesoblast: Recruitment Commenced For NIH Supported Phase 2/3 Trial Of Remestemcel-L In COVID-19 Acute Respiratory Distress Syndrome - Seeking Alpha - May 21st, 2020
- Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferation in vivo - Science Advances - May 21st, 2020
- Adult Stem Cells 101 Boston Children's Hospital - May 16th, 2020
- Revealed: First trial of pioneering stem-cell treatment for heart disease performed in China - Nature.com - May 14th, 2020
- Adult Stem Cells - May 14th, 2020
- Dlp-mediated Hh and Wnt signaling interdependence is critical in the niche for germline stem cell progeny differentiation - Science Advances - May 14th, 2020
- CTX001 for Treatment of Sickle Cell Disease and Other Blood Disorders - Sickle Cell Anemia News - May 14th, 2020
- Australia's Mesoblast raises $90M to scale up stem cell therapy manufacturing to treat COVID-19 ARDS - BioWorld Online - May 14th, 2020
- Stem cells therapy A prospective treatment against coronavirus? - Daily Excelsior - May 14th, 2020
- Merck's KEYTRUDA (pembrolizumab) Superior to Brentuximab Vedotin (BV), a Standard of Care, in Patients With Classical Hodgkin Lymphoma (cHL) in... - May 14th, 2020
- Adult Stem Cell - an overview | ScienceDirect Topics - May 12th, 2020
- Altered Bone Marrow Microenvironment Induces Defect of Hematopoietic Stem Cells in -thalassemia - Hematology Advisor - May 12th, 2020
- Stemline Slated for Acquisition by Menarini in Deal Worth Up to $677M - Xconomy - May 9th, 2020
- Rituximab Offers No Extra Benefit to Induction Chemo in ALL - Medscape - May 9th, 2020
- Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome - The Lancet - May 9th, 2020
- BrainStorm Leases a New Cleanroom Facility at The Tel Aviv Sourasky Medical Center to Manufacture NurOwn for The European Union - StreetInsider.com - May 9th, 2020
- Weekly pick of brain tumour research news from around the world - Brain Tumour Research - May 9th, 2020
- BrainStorm Leases a New Cleanroom Facility at The Tel Aviv Sourasky Medical Center to Manufacture NurOwn for The European Union - BioSpace - May 7th, 2020
- Here's Why Athersys Tumbled 23.3% in April - The Motley Fool - May 7th, 2020
- What is the Value of iPSC Technology in Cardiac... - The Doctor Weighs In - May 7th, 2020
- Schizophrenia drug points to improved brain cancer radiation therapy - New Atlas - May 7th, 2020
- Merck to Present New Data from its Broad Oncology Portfolio and Pipeline at the ASCO20 Virtual Scientific Program - Maryville Daily Times - May 7th, 2020
- What Do New Neurons in the Brains of Adults Actually Do? - The Scientist - May 7th, 2020
- Scientists finally explained one of the strangest coronavirus symptoms - BGR - May 7th, 2020
- Teva and Celltrion Healthcare Announce the Launch of TRUXIMA (rituximab-abbs) Injection for Rheumatoid Arthritis, the Only Biosimilar to Rituxan... - May 7th, 2020
- Genmab Announces U.S. FDA Approval of Subcutaneous Formulation of Daratumumab, DARZALEX FASPRO (daratumumab and hyaluronidase-fihj), for the Treatment... - May 3rd, 2020
- CHMP Issues Positive Opinion Recommending Subcutaneous Formulation of Daratumumab for the Treatment of Patients with Multiple Myeloma - Yahoo Finance - May 1st, 2020
- BrainStorm-Cell Therapeutics to Announce First Quarter Financial Results and Provide a Corporate Update - StreetInsider.com - May 1st, 2020
- Adult Stem Cells | HowStuffWorks - April 30th, 2020
- Adult stem cell - Wikipedia - April 30th, 2020
- Stem Cell Basics IV. | stemcells.nih.gov - April 30th, 2020
- Where Do We Get Adult Stem Cells? - Children's Hospital - April 30th, 2020
- Chimerix Announces Initiation of a Phase 2/3 Study of DSTAT in Acute Lung Injury for Patients with Severe COVID-19 - StreetInsider.com - April 29th, 2020
- US bishop: We must halt development of any coronavirus vaccine derived from aborted babies - Lifesite - April 29th, 2020