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

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.