Journal Article

A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma

Li, Chenggong, Wang, Zhihui, Jiang, Huiwen, Xia, Yimeng, Deng, Jun, Chen, Lei, Zhao, Xinying, Mei, Heng, Kou, Haiming, Liu, Lin, Hua, Gaoquan, Yin, Ping, Ke, Sha, Tang, Lu, Ai, Lisha, Jin, Dan, Sun, Chunyan, Huang, Zhiping, Xia, Linghui, Guo, Tao, Cai, Li, Hu, Yu

2021

Overview

Background BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations. Methods We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial. Results BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1–2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10 –4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months. Conclusion Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM. Trial registration : Chictr.org.cn ChiCTR1800018143.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animal models / Antibodies / Antigens / B cells / BCMA / Bispecific CAR / Cancer Research / CD38 / CD38 antigen / Cell therapy / Chimeric antigen receptor-T cells / Chimeric antigen receptors / Clinical trials / Cytokines / Cytotoxicity / Diseases / First-in-human clinical trials for cancer and blood disorders / Genotype & phenotype / Hematology / Immunotherapy / Leukopenia / Lymphocytes / Lymphocytes T / Manufacturers / Medical prognosis / Medicine / Medicine & Public Health / Minimal residual disease / Mortality / Multiple myeloma / Neurotoxicity / Neutropenia / Oncology / Patients / Plasmacytoma / Relapse / T cells / Thrombocytopenia / Values / Xenografts