Long-term outcomes following CAR T cell therapy: what we know so far

Abstract

Chimeric antigen receptors (CAR) are engineered fusion proteins designed to target T cells to antigens expressed on cancer cells. CAR T cells are now an established treatment for patients with relapsed and/or refractory B cell lymphomas, B cell acute lymphoblastic leukaemia and multiple myeloma. At the time of this writing, over a decade of follow-up data are available from the initial patients who received CD19-targeted CAR T cells for B cell malignancies. Data on the outcomes of patients who received B cell maturation antigen (BCMA)-targeted CAR T cells for multiple myeloma are more limited owing to the more recent development of these constructs. In this Review, we summarize long-term follow-up data on efficacy and toxicities from patients treated with CAR T cells targeting CD19 or BCMA. Overall, the data demonstrate that CD19-targeted CAR T cells can induce prolonged remissions in patients with B cell malignancies, often with minimal long-term toxicities, and are probably curative for a subset of patients. By contrast, remissions induced by BCMA-targeted CAR T cells are typically more short-lived but also generally have only limited long-term toxicities. We discuss factors associated with long-term remissions, including the depth of initial response, malignancy characteristics predictive of response, peak circulating CAR levels and the role of lymphodepleting chemotherapy. We also discuss ongoing investigational strategies designed to improve the length of remission following CAR T cell therapy.

Fig. 1. 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 antigen-binding 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-chain-only 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.

Fig. 2. Investigational strategies designed to improve remission duration following CAR T cell therapy.

The process of chimeric antigen receptor (CAR) T cell therapy involves harvesting peripheral blood mononuclear cells from a patient by apheresis, followed by transduction with viruses encoding the CAR, ex vivo T cell expansion, and re-infusion into the patient after completion of lymphocyte-depleting chemotherapy. Studies attempting to optimize each step of this process, and thus improve the durability of remissions following CAR T cell therapy, are currently ongoing. H/T, hinge and transmembrane; scFv, single-chain variable fragment; RRMM, relapsed and/or refractory multiple myeloma; T_SCM, stem central memory T.