CAR T cell therapy in autoantibody-mediated neurological disorders: a promising strategy

TL;DR

CAR T cell therapy is being explored as a potential treatment for neurological disorders caused by harmful autoantibodies, offering a targeted way to eliminate disease-causing B cells.

Contribution

The paper introduces a classification of CAR T cell therapies tailored to different autoantibody-mediated neurological disorders and discusses their therapeutic potential.

Findings

CAR T cell therapy can selectively target and eliminate autoreactive B cells in autoimmune neurological disorders.

Different CAR T strategies are proposed based on the type of autoantigen involved in the disease.

Safety concerns and neurotoxicity remain key challenges for clinical application.

Abstract

Chimeric antigen receptor (CAR) T cell therapy is emerging as a promising approach for B cell-driven neurological autoimmune disorders, particularly those characterized by pathogenic autoantibodies that target key neural structures. These conditions, including neuromyelitis optica spectrum disorder, myasthenia gravis, Lambert-Eaton myasthenic syndrome, MOG antibody-associated disease, anti-NMDA receptor encephalitis, Diacylglycerol lipase alpha antibody associated encephalitis, stiff person syndrome, and multiple sclerosis, can be categorized based on their primary autoantigens into (1) extracellular antigen-associated (e.g., AQP4, AChR, NMDAR, MOG, VGCC), (2) intracellular antigen-associated (e.g., GAD65, DAGLA), or (3) unidentified antigenic origin (as seen in multiple sclerosis). This distinction is essential for guiding therapeutic strategies and exploring novel principles represented in distinct treatment approaches and their corresponding therapeutic outcomes.

In this review, we propose a classification of CAR T cell therapies designed for different target antigens, including: CD19/20/BCMA-directed CAR T cells targeting general B cell-mediated pathogenesis, regulatory T cells modified with CARs, and the design of chimeric autoantibody receptors (CAARs) to selectively deplete pathogenic B cells directly associated with disease progression while preserving immune tolerance. We further discuss preclinical and clinical advancements, key challenges such as safety concerns and neurotoxicity, and the future landscape of CAR T applications in neuromyelitis optica spectrum disorder, myasthenia gravis, Lambert-Eaton myasthenic syndrome, MOG antibody-associated disease, anti-NMDA receptor encephalitis, Diacylglycerol lipase alpha antibody associated encephalitis, stiff person syndrome, and multiple sclerosis according to the latest research, case and trial data.

CAR T cell therapy potentially offers a highly specific and effective method with thorough elimination of autoreactive B cells, representing a rapidly evolving field with the potential to transform the treatment of autoimmune neurological disorders. As CAR T technology advances, it holds the potential to become a groundbreaking immunoablative strategy with so-far disclosed controllable side effects; however, further long-term follow-up data are still needed to validate its application in autoimmune disorders.

Figures