CAR T-cell therapy for multiple myeloma: state of the art and prospects

Abstract

Chimeric antigen receptors (CAR) are fusion proteins containing an antigen-recognition domain coupled to a T-cell activation domain (eg, CD3ζ [CD247]) and to a costimulatory domain (eg, CD28 or 4-1BB [TNFRSF9, also known as CD137]). The B-cell maturation antigen (BCMA; TNFRSF17) is an attractive target for CAR T-cell therapy because it is only expressed by normal and malignant plasma cells and by a subset of mature B cells. Several trials of anti-BCMA CAR T cells have shown high-quality responses, including minimal residual disease-negativity in patients with multiple myeloma who were heavily pretreated. Phase 3 trials are currently evaluating CAR T-cell therapy versus standard-of-care regimens in patients in earlier stages of the disease. Trials are also ongoing in newly diagnosed patients with high-risk cytogenetic profiles or with residual disease after transplantation. CAR T cells targeting other multiple myeloma antigens, such as CD19, CD38, CD138 (SYND1), and SLAMF7, are also being explored. Toxicities associated with CAR T cells include cytokine-release syndrome, different types of cytopenia, infections, and neurotoxicity. Although some subsets of patients have sustained responses for more than 1 year, most patients eventually relapse, which might be related to the loss of CAR T cells, loss of antigen expression on the tumour cell surface, or to an immunosuppressive microenvironment that impairs the activity of T cells. Efforts to improve the effectiveness of CAR T-cell therapy include optimising CAR design and adapting the manufacturing process to generate cell products enriched for specific subsets of T cells (eg, early memory cells). Other strategies explored in trials include dual-antigen targeting to prevent antigen escape and rational combination therapy to enhance persistence. Several approaches are also being developed to improve the safety of CAR T-cell therapy, such as the incorporation of a suicide gene safety system.