Chimeric antigen receptor T-cell therapies for multiple myeloma

Abstract

Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR-T cells (CAR-Ts) against leukemia and lymphoma has encouraged development of CAR-T therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen is expressed by normal and malignant plasma cells. CAR-Ts targeting B-cell maturation antigen have demonstrated significant antimyeloma activity in early clinical trials. Toxicities in these trials, including cytokine release syndrome, have been similar to toxicities observed in CAR-T trials for leukemia. Targeting postulated CD19+ myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte–activating molecule 7, and κ light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of >1 antigen might often be required for effective treatment of MM with CAR-Ts. Integration of CAR-Ts with other myeloma therapies is an important area of future research. CAR-T therapies for MM are at an early stage of development but have great promise to improve MM treatment.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…BCMA is a normal plasma cells marker, falls in to the near-ideal antigen for multiple myeloma with no evidence of expression on the normal non-hematological tissue [144]. Latest multi-center BCMA-CAR trials results indicate a relatively safe profile (although cytokine release syndrome -CRS and transient neurotoxicity were observed) with an overall response rate over 90% [145,146].…”

“…Latest multi-center BCMA-CAR trials results indicate a relatively safe profile (although cytokine release syndrome -CRS and transient neurotoxicity were observed) with an overall response rate over 90% [145,146]. Other antigens currently being targeted to treat hematological malignancies include CD20 for NHL, CD138 for MM [144], CD33 [147], CD123 for AML [148,149] and CD7 for certain leukemias and lymphomas [150]. Lately, using a very elegant approach to treat T-cell malignancies, Pule and colleagues isolated an antibody specific for the TCRβ1 constant region.…”

B cell maturation antigen‐specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: A meta‐analysis

“…While ligation of BCMA promotes myeloma cell proliferation and drug resistance, antibody‐based blockade of BCMA signaling has resulted in some preclinical anti‐MM activity . Thus, BCMA is a rational target for antimyeloma therapy using CAR T cells …”

“…20 Thus, BCMA is a rational target for antimyeloma therapy using CAR T cells. 12,21 Several groups have investigated the role of anti-BCMA CAR T-cell therapy in RRMM over recent years. Here, we aim to systematically review the current literature and to summarize results of anti-BCMA CAR T-cell therapies with regard to efficacy and safety in patients with RRMM.…”

A review of chimeric antigen receptor T-cells in lymphoma

“…Clinical trials in multiple myeloma targeting B-cell maturation antigen (BCMA) have proven efficacy and safety of the use of CAR-T in this population [64]. Signaling lymphocyte-activating molecule F7 (SLAMF7), the monoclonal antibody target of elotuzumab, is another promising target in multiple myeloma given its lack of expression outside of hematologic cell line; however, CAR-T targeting this antigen has yet to be used in human clinical trials [65,66]. Many trials of CAR-T in multiple myeloma have shown consistent clinical response but optimization of dose and optimal target antigen still require refinement.…”