Li Jiaqian, Guo Rongbing, Li Dan, Yang Jinrong, Zhang Yalan, Gao Haozhan, Yang Yuening, Wang Fengling, Niu Ting, Wang Wei
Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan Province, People's Republic of China.
Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan Province, People's Republic of China; College of Life Sciences, Sichuan University, Chengdu 610041 Sichuan Province, People's Republic of China.
Int Immunopharmacol. 2025 Feb 20;148:114113. doi: 10.1016/j.intimp.2025.114113. Epub 2025 Jan 24.
Chimeric antigen receptor T (CAR-T) cell therapy targeting B cell mature antigen (BCMA) has shown remarkable clinical benefits in treating multiple myeloma (MM). Bortezomib, a proteasome inhibitor approved as a first-line agent for MM for two decades, has demonstrated potent antitumor activity. In this study, we found that bortezomib treatment stabilizes the expression of BCMA and conceived the hypothesis that BCMA CAR-T therapy combined with bortezomib would enhance the anti-MM efficacy. The in vitro experiments revealed that pretreatment of both MM tumor cell line MM1.S and tumor cell line NALM-6 forced expression of BCMA with low concentrations of bortezomib up-regulated BCMA expression. When encountered with BCMA CAR-T cells, the cytotoxicity to these bortezomib-treated tumor cells was increased, indicating that the up-regulated BCMA induced by bortezomib contributes to the enhanced activities of the CAR-T cells. Further, in the in vivo experiment, the combined treatment significantly enhanced the anti-MM ability and prolonged the survival rate. Moreover, safety analysis found that there is no tissue damage or loss of weight, suggesting the favorable tolerability of this combination strategy. Our study provided a surety and efficacious strategy for the BCMA-targeted CAR-T cancer immunotherapy enhancement.
靶向B细胞成熟抗原（BCMA）的嵌合抗原受体T（CAR-T）细胞疗法在治疗多发性骨髓瘤（MM）方面已显示出显著的临床疗效。硼替佐米是一种蛋白酶体抑制剂，二十年来一直被批准作为MM的一线治疗药物，已证明具有强大的抗肿瘤活性。在本研究中，我们发现硼替佐米治疗可稳定BCMA的表达，并提出了BCMA CAR-T疗法联合硼替佐米可增强抗MM疗效的假设。体外实验表明，用低浓度硼替佐米预处理MM肿瘤细胞系MM1.S和肿瘤细胞系NALM-6的BCMA强制表达，可上调BCMA表达。当与BCMA CAR-T细胞相遇时，对这些经硼替佐米处理的肿瘤细胞的细胞毒性增加，表明硼替佐米诱导的BCMA上调有助于增强CAR-T细胞的活性。此外，在体内实验中，联合治疗显著增强了抗MM能力并延长了存活率。此外，安全性分析发现没有组织损伤或体重减轻，表明这种联合策略具有良好的耐受性。我们的研究为增强靶向BCMA的CAR-T癌症免疫疗法提供了一种可靠且有效的策略。
