Duan Deming, Wang Keke, Wei Cheng, Feng Dudu, Liu Yonghua, He Qingyan, Xu Xing, Wang Chunling, Zhao Shuping, Lv Leili, Long Jing, Lin Danni, Zhao Ai, Fang Bingmu, Jiang Jinhong, Tang Shixing, Gao Jimin
Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.
Front Immunol. 2021 Mar 5;12:609421. doi: 10.3389/fimmu.2021.609421. eCollection 2021.
Chimeric antigen receptor (CAR) technology has revolutionized cancer treatment, particularly in malignant hematological tumors. Currently, the BCMA-targeted second-generation CAR-T cells have showed impressive efficacy in the treatment of refractory/relapsed multiple myeloma (R/R MM), but up to 50% relapse remains to be addressed urgently. Here we constructed the BCMA-targeted fourth-generation CAR-T cells expressing IL-7 and CCL19 (i.e., BCMA-7 × 19 CAR-T cells), and demonstrated that BCMA-7 × 19 CAR-T cells exhibited superior expansion, differentiation, migration and cytotoxicity. Furthermore, we have been carrying out the first-in-human clinical trial for therapy of R/R MM by use of BCMA-7 × 19 CAR-T cells (ClinicalTrials.gov Identifier: NCT03778346), which preliminarily showed promising safety and efficacy in first two enrolled patients. The two patients achieved a CR and VGPR with Grade 1 cytokine release syndrome only 1 month after one dose of CAR-T cell infusion, and the responses lasted more than 12-month. Taken together, BCMA-7 × 19 CAR-T cells were safe and effective against refractory/relapsed multiple myeloma and thus warranted further clinical study.
嵌合抗原受体（CAR）技术彻底改变了癌症治疗方式，尤其是在恶性血液肿瘤治疗中。目前，靶向B细胞成熟抗原（BCMA）的第二代CAR-T细胞在治疗难治性/复发性多发性骨髓瘤（R/R MM）方面已显示出令人瞩目的疗效，但仍有高达50%的复发情况亟待解决。在此，我们构建了表达白细胞介素-7（IL-7）和C-C基序趋化因子配体19（CCL19）的靶向BCMA的第四代CAR-T细胞（即BCMA-7×19 CAR-T细胞），并证明BCMA-7×19 CAR-T细胞表现出卓越的增殖、分化、迁移和细胞毒性。此外，我们一直在开展使用BCMA-7×19 CAR-T细胞治疗R/R MM的首例人体临床试验（ClinicalTrials.gov标识符：NCT03778346），该试验在前两名入组患者中初步显示出有前景的安全性和疗效。这两名患者在一剂CAR-T细胞输注仅1个月后就达到了完全缓解（CR）和非常好的部分缓解（VGPR），且仅有1级细胞因子释放综合征，缓解持续时间超过12个月。综上所述，BCMA-7×19 CAR-T细胞在治疗难治性/复发性多发性骨髓瘤方面安全有效，因此值得进一步开展临床研究。
