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

Abstract

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.