Engineering our own immune cells to attack cancer, once the plot of science fiction, is now an evolving standard of care, transforming the treatment paradigms for many hematologic malignancies. It even has a perfect sci-fi name – chimeric antigen receptor T cells (CAR-Ts) Since their initial development in the early 1990s by Drs. Zelig Eshhar and Gideon Gross, five CAR-T products have been approved by the U.S. Food and Drug Administration for relapsed B-cell lymphomas, B-cell acute lymphoblastic leukemia (ALL), and multiple myeloma. Their names may be a mouthful, but their efficacies are undisputable. Understanding the nuanced anatomy of CAR-Ts is important for hematologists, and for this reason, watching the prerecorded videos and attending Monday’s virtual and in-person live Q&A session, “Novel Findings in CAR T-cell Therapies for Hematologic Malignancies,” should be on everyone’s calendar. In the session, Dr. Marcela Maus from Massachusetts General Hospital speaks about CAR-T (signaling) mechanisms, Dr. David Baker from University of Washington presents on modulation and prediction of protein-protein interactions, and Dr. Marco Ruella from University of Pennsylvania presents resistance mechanisms to CAR-Ts in ALL and lymphoma.
CAR-Ts use autologous (derived from the patient) T-lymphocytes that are genetically modified to express CARs. CARs come in many flavors but are typically composed of a ligand-based (such as BCMA) or single-chain variable fragment domain (FAB) that targets tumor antigen (such as CD19), hinge and transmembrane domain, costimulatory domain (CD28 or 4-1BB), and T-cell activation (intracellular signaling) domain. These modified T cells target the neoplastic cells, and upon binding antigen, are activated (with the help of the costimulatory domain). This results in the CAR-Ts (hopefully) eliminating target tumor cells. First-generation CAR-Ts lacked costimulatory domains and failed to demonstrate any clinically meaningful activity. The introduction of costimulatory domains resulted in more potent T-cell activation and proliferation leading to improved clinical efficacy. Second-generation CAR-Ts have either CD28 (axicabtagene ciloleucel and brexucabtagene autoleucel) or 4-1BB (tisagenlecleucel, lisocabtagene maraleucel, and idecabtagene vicleucel) costimulatory domains. It is postulated that the toxicity profiles differ amongst products based on the type of costimulatory domain. However, there is currently no clear preferred costimulatory domain. Third-generation CAR-Ts incorporate both costimulatory domains; however, it is unknown if this will result in more efficacy and/or toxicity.
Dr. Maus described her work in improving various CAR-T constructs. She discussed promising efficacy of targeting the CD37, an antigen expressed on T-cell and acute myeloid leukemia cells. Anti-CD37 CAR-Ts had meaningful efficacy in cutaneous T-cell lymphoma and acute myeloid leukemia. She also discussed a ligand-based construct with chimeric soluble APRIL (triPRIL), which targets both BCMA and the related protein, TACI. A pre-clinical study demonstrated that the triPRIL CAR-T was effective against multiple myeloma cells that were BCMA negative, and a phase I study evaluating this CAR-T construct is currently accruing patients.
Dr. Maus also discussed the role of interferon γ in CAR-T function and cytokine release syndrome (CRS). Blockade of interferon γ did not impair the function of CD19 and BCMA CAR-Ts but may be able to reduce the severity of CRS in mouse models.
Dr. Baker discussed utilizing computational protein design to modulate and predict protein-protein design. He described his work in predicting protein structures to build new proteins that can be applied to CAR-T recruitment based on specific surface markers. For example, a CAR-T can be recruited when two specific surface markers are expressed on the given cell (cage and key method), but not recruited when a specific marker (perhaps a normal cell surface marker) is expressed.
Despite the remarkable efficacy of CAR-Ts, relapse is still common. There are multiple factors that cause relapse, including pre-infusion barriers, CAR-T dysfunction, tumor intrinsic mechanisms, and tumor microenvironment. Dr. Rubella further explained postulated mechanisms. He described how loss of extrinsic apoptotic pathway (death receptor signaling) in the tumor confers resistance to CAR-Ts. Another mechanism is loss of CD19 antigen in the tumor cells treated with anti-CD19 CAR-Ts. Interestingly, antibiotic use before CAR-T infusion correlated with poor outcome (decreased progression-free survival and increased CRS and neurotoxicity), likely by affecting gut microbiota.
In addition to these amazing Education Program sessions, potentially practice-changing clinical trial results involving CAR-T therapies will be presented at the 2021 ASH Annual Meeting. The eagerly awaited results of the ZUMA-7 trial will be presented during the Plenary Scientific session. This trial compared axicabtagene ciloleucel versus standard of care autologous stem cell transplantation in relapsed/refractory B-cell lymphoma. Oral abstract #91 compares a different CAR-T product (lisocabtagene maraleucel) versus autologous stem cell transplantation in relapsed/refractory B-cell lymphoma.
So, all hematologists, get ready to find the key to the CAR.
Dr. Jeong and Dr. Goodman indicated no relevant conflicts of interest.
