开发靶向 SEMA4A 的 CAR-T 细胞以克服多发性骨髓瘤中的低 BCMA 抗原密度

Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) is effective, but relapses associated with low-to-negative BCMA expression are common, indicating the need for additional targets.

We quantitatively profile antigen density in a cohort of patients relapsed after BCMA CAR T therapy, showing high number of SEMA4A molecules/cell where BCMA density is low. SEMA4A deletion limits MM cell growth, migration, tissue infiltration, and osteoclast formation, while extending mouse survival.

We generate monoclonal antibodies targeting SEMA4A-extracellular domain for CAR construction, screen engineered T cells for expansion, cytokine release, and cytotoxicity against MM cells. Lead constructs lack reactivity against normal non-hematopoietic tissues. SEMA4A CAR T cells show superior efficacy than BCMA CAR T cells eliminating patient-derived BCMA low tumors and MM cells progressing under suboptimal doses of BCMA CAR T cells.

This study prepares for a phase 1 clinical trial with SEMA4A-directed CAR T cells for MM.