Targeting human plasma cells using small molecule regulated BCMA CAR T cells eliminates circulating antibodies in humanized mice.

Abstract

Pathogenic long-lived plasma cells (LLPCs) secrete autoreactive antibodies, exacerbating autoimmune diseases and complicating solid organ transplantation. Targeted elimination of the autoreactive B-cell pool represents a promising therapeutic strategy, yet current treatment modalities fall short in depleting mature plasma cells. Here, we demonstrate that chimeric antigen receptor (CAR) T cells, targeting BCMA utilizing a split-receptor design, offer a controlled and effective therapeutic strategy against LLPCs. Dimerizing agent-regulated immune-receptor complex (DARIC) T cells demonstrated robust rapamycin-dependent targeting of tumor and plasma cells. Notably, in humanized mouse models, DARIC-T cells regulated peripheral human immunoglobulin levels through specific elimination of human LLPCs from the bone marrow. Furthermore, DARIC constructs were efficiently integrated into the T-cell receptor α constant (TRAC) locus while maintaining potent antigen-specific cytotoxicity. These findings underscore the potential of split-receptor CAR T cells in autoimmune and transplant medicine, highlighting their versatility in applications beyond oncology.