The Promise of CAR T-Cells: Progress and Challenges in Cancer Immunotherapy

CAR T-cell therapy has shown remarkable potential to cure some patients with advanced blood cancers who have exhausted standard treatment options. By engineering a patient’s own immune T-cells to target specific cancer antigens, this personalized form of immunotherapy harnesses the body’s natural defenses to seek and destroy tumor cells. Over a decade since the first clinical trials began, long-term follow-up data have affirmed CAR T-cells’ ability to induce durable remissions in certain patients. However, the therapy also faces challenges, as not all treated cancers respond equally well and toxicity remains a concern. Ongoing research aims to optimize various aspects of CAR T-cell treatment to improve outcomes on a broader scale.

In their comprehensive review, Drs. Kathryn Cappell and James Kochenderfer of the National Cancer Institute analyze long-term data from hundreds of patients with B-cell lymphomas, leukemias, and multiple myeloma who received approved CD19- or BCMA-targeted CAR T-cell therapies in clinical studies. Overall response rates exceeded 70% for most indications, with complete remissions over 50% in many trials. Crucially, some patients across all treated cancers experienced remissions lasting several years or more without additional therapy.

Notably for B-cell lymphomas, follow-up out to a decade post-treatment indicated a portion of patients were likely cured by CAR T-cells alone. Remission durations in large B-cell lymphoma even rivaled or exceeded outcomes with intensive chemotherapy plus stem cell transplantation. This establishes CAR T-cells as a potentially curative option for relapsed/refractory lymphomas, changing the treatment paradigm.

Kathryn M. Cappell & James N. Kochenderfer

FDA-approved CAR T cell therapies. A total of six chimeric antigen receptor (CAR) products are currently available commercially, including four for patients with B cell lymphomas, two for patients with B cell acute lymphoblastic leukaemia (B-ALL) and two for those with multiple myeloma (MM). All approved products have a second-generation CAR construct, consisting of an antigenbinding domain, a hinge region, a transmembrane region, a co-stimulatory domain and a T cell activation domain. All CD19-targeted CARs contain the same antigen-binding domain, which is a single-chain variable fragment derived from the mouse FMC63 monoclonal antibody. Axicabtagene ciloleucel and brexucabtagene autoleucel use the same CAR but differ in their manufacturing processes, with production of brexucabtagene autoleucel including an additional step designed to remove malignant cells from the leukapheresis product. Tisagenlecleucel differs from these products in that it contains different hinge and transmembrane domains and includes a 4-1BB domain instead of a CD28 domain for co-stimulation. Lisocabtagene maraleucel is delivered at a defined CD4+:CD8+ T cell composition. The CAR gene for axicabtagene ciloleucel and brexucabtagene autoleucel is delivered using a gammaretrovirus, whereas those for tisagenlecleucel and lisocabtagene maraleucel are delivered using lentiviruses. Idecabtagene vicleucel includes a mouse 11D5-3 single-chain variable fragment targeting B cell maturation antigen (BCMA). Ciltacabtagene autoleucel has a binding domain consisting of two linked camelid heavy-chainonly variable (VHH) antigen-binding domains targeting BCMA. In both products, the CAR gene is delivered using a lentivirus. FL, follicular lymphoma; HSCT, haematopoietic stem cell transplantation; LBCL, large B cell lymphoma; MCL, mantle cell lymphoma; R/R, relapsed and/or refractory.

In contrast, while acute lymphoblastic leukemia (ALL) and multiple myeloma saw very high response rates from CAR T-cells, fewer achieved durable remissions without consolidative stem cell transplantation or additional therapies. This suggests CAR T-cells alone may not provide a cure for these cancers as often. The nuanced differences in long-term efficacy underscore how CAR T-cell therapy’s impact can vary depending on tumor characteristics.

Analyzing predictive factors, the review confirms deeper initial responses—measured by degree of tumor shrinkage or molecular minimal residual disease testing—were most strongly linked to prolonged remissions across all treated cancers. Lower disease burden prior to treatment also correlated with better durability. Encouragingly, some patients with myeloma attained remissions lasting years from BCMA-targeted CAR T-cells, showing promise for this application as well.

In terms of safety, while acute toxicity risks like cytokine release syndrome and neurotoxicity are well-known, the review finds late adverse events were generally less common than during initial treatment. Persistent but manageable low blood counts occurred in 15-20% of cases depending on prior therapies. Reactivation of viral infections post-therapy also appeared uncommon beyond one month post-infusion.

Perhaps the most prevalent and challenging long-term issue was B-cell aplasia induced by CD19-targeted therapies. Up to 38% of lymphoma survivors demonstrated ongoing depletion of normal B-cells years later, necessitating lifelong immunoglobulin replacement. Moreover, secondary malignancies emerged in 15% of treated patients—similar to expected chemotherapy-related risks rather than a red flag for gene therapy concerns from viral vector integration.

Given these insights, the review outlines active research strategies addressing different aspects of the treatment process, aiming to build on CAR T-cell therapy’s successes while minimizing issues. Dual-targeting of separate tumor antigens seeks to prevent antigen escape that sometimes underlies relapse. Fully human CAR designs may improve persistence by evading anti-non-human immune responses. Optimizing lymphodepleting regimens and earlier treatment timepoints aim to maximize CAR T-cell expansion. Co-administering agents like immune checkpoint inhibitors may aid persistence against immunosuppressive tumor microenvironments.

Overall, the review underscores CAR T-cell therapy’s potential to revolutionize certain hard-to-treat blood cancers. Yet realizing this vision fully will require continued innovation across all aspects of treatment—from optimizing patient selection to enhancing CAR T-cell potency and durability. With further refinement, this personalized cell therapy may one day offer hope for cure to many more cancer patients worldwide.