CAR T-Cell Immunotherapy in Neuroautoimmune Diseases: Focus on the Central Nervous System

In the early days, the treatment of central nervous system (CNS) autoimmune diseases relied exclusively on broadly acting immunosuppressants. Since the 1960s, high-dose corticosteroids and conventional systemic immunosuppressants were used to treat relapses in Multiple Sclerosis (MS), with substantial toxicity and increased risk of infections and development of malignancies, due to chronic immunosuppression. Disease-modifying therapies (DMTs) were first introduced in the early 1990s in MS, the prototypical CNS autoimmune disorder, with interferon-beta. They later expanded in the mid 2000s with monoclonal antibodies (mAbs). Compared to previously used systemic immunosuppressants, DMTs allow for the selective depletion of cellular targets and cytokines. B-cell–depleting mAbs became central DMTs in CNS autoimmunity, as B-cells contribute significantly to the pathophysiology of all major CNS autoimmune diseases, including MS, Neuromyelitis Spectrum Disorders (NMOSD), Myelin Oligodentrocyte Glycoprotein Antibody‑Associated Disease (MOGAD), and Autoimmune Encephalitides (AE). However, mAb-based therapies require repeated dosing and have limited tissue penetration. This constitutes them unable to eliminate critical cells residing within isolated or protected microenvironments including the CNS. Chimeric antigen receptor (CAR) T cells are a “living” therapy engineered to eliminate antigen-specific cells, offering deep, potentially durable depletion, after a single treatment, able to access currently mAb-inaccessible targets. In this review, we evaluate CAR T-cell therapies in the context of CNS autoimmunity, with the necessary historical prism. We describe possible differential targets (mainly B-cell subsets) according to each disease, describe preclinical studies involving alternative CAR T-cell products, report clinical experience in 15 patients, and outline ongoing or planned trials.