• Jie Xu, Li-Juan Chen, Shuang-Shuang Yang, Yan Sun, Wen Wu, Yuan-Fang Liu, Ji Xu, Yan Zhuang, Wu Zhang, Xiang-Qin Weng, Jing Wu, Yan Wang, Jin Wang, Hua Yan, Wen-Bin Xu, Hua Jiang, Juan Du, Xiao-Yi Ding, Biao Li, Jun-Min Li, Wei-Jun Fu, Jiang Zhu, Li Zhu, Zhu Chen, Xiao-Hu Frank Fan, Jian Hou, Jian-Yong Li, Jian-Qing Mi, and Sai-Juan Chen.
• State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
• Proc. Natl. Acad. Sci. U.S.A. 2019 May 7; 116 (19): 9543-9551.

AbstractRelapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.

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