Leveraging chimeric antigen receptor-T cell therapy for the treatment of multiple sclerosis: Bridging oncology and neurology.

Multiple sclerosis (MS) is driven by complex interactions among B cells, autoreactive T cells, and compartmentalized inflammation behind the blood-brain barrier (BBB). Although treatment with B cell-targeting monoclonal antibodies (mAbs) has transformed MS management, their efficacy remains limited by inadequate penetration into the central nervous system (CNS), incomplete depletion of long-lived plasma cells, and development of treatment resistance in a significant number of patients. In recent years, chimeric antigen receptor (CAR)-T cell therapy has emerged as a new therapeutic approach to reset pathogenic immune circuits in MS. CAR-T cell therapy enables more profound and durable depletion of pathogenic B cell populations and, potentially, CNS-associated antibody-producing cells, allowing partial reconstitution of a more tolerant and less autoreactive humoral immune system and reducing intrathecal antibody-mediated inflammation. However, the extent to which CAR-T cells can eradicate deeply compartmentalized CNS-resident immune populations remains under investigation. Nonetheless, CAR-T cell therapy for MS has evolved beyond B cell-depleting strategies, and other types of CAR-T cell therapies with distinct mechanisms of action have also been developed. These strategies include chimeric autoantibody receptor (CAAR)-T cell therapy for selective depletion of autoreactive B cells, CAR-engineered regulatory T (CAR-Treg) cells to restore localized immune tolerance, and T cell receptor mimic CAR-T cells (TCRm CAR-T cells) to recognize autoantigenic peptide-MHC complexes. This review aims to discuss the progress of CAR-T cell therapy for MS and its existing challenges, including safety concerns, optimal antigen selection, and safe access to the CNS. Advances in dual-targeting strategies, chemokine receptor engineering, allogeneic platforms, tailoring strategies to the heterogeneous immunopathology of MS, and in vivo generation of CAR-T cells are also comprehensively discussed.