Bortezomib enhances the efficacy of BCMA CAR-T therapy through up-regulating BCMA expression in myeloma cells

Jiaqian Li; Rongbing Guo; Dan Li; Jinrong Yang; Yalan Zhang; Haozhan Gao; Yuening Yang; Fengling Wang; Ting Niu; Wei Wang

doi:10.1016/j.intimp.2025.114113

Bortezomib enhances the efficacy of BCMA CAR-T therapy through up-regulating BCMA expression in myeloma cells

Int Immunopharmacol. 2025 Jan 24:148:114113. doi: 10.1016/j.intimp.2025.114113. Online ahead of print.

Authors

Jiaqian Li¹, Rongbing Guo², Dan Li¹, Jinrong Yang³, Yalan Zhang¹, Haozhan Gao¹, Yuening Yang¹, Fengling Wang¹, Ting Niu⁴, Wei Wang⁵

Affiliations

¹ 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.
² 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.
³ 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; Hematology Research Laboratory, Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan Province, People's Republic of China.
⁴ Hematology Research Laboratory, Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 Sichuan Province, People's Republic of China.
⁵ 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. Electronic address: weiwang@scu.edu.cn.

PMID: 39862629
DOI: 10.1016/j.intimp.2025.114113

Abstract

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.

Keywords: BCMA; Bortezomib; CAR-T cell; Immunotherapy; Multiple myeloma.