Chimeric Antigen Receptor T‐Cell Therapy in Multiple Sclerosis: Rationale, Mechanisms, and Clinical Perspectives

ABSTRACT

To systematically review the emerging clinical evidence on CAR‐T cell therapy in adults with multiple sclerosis, including relapsing–remitting and progressive phenotypes, with particular emphasis on safety, clinical outcomes, biological effects, and evidence of CNS activity. Multiple Sclerosis is a progressive neuroinflammatory disease caused due to autoimmune assault on the central nervous system. Despite the earliest description being found in the 14th century, the autoimmune nature of MS was only confirmed in the 1960s. The discovery of Interferon Beta‐1b, a DMT, was revolutionary in reducing the frequency of exacerbations in MS. However, there remains a lacuna in the treatment of MS that focuses on neuroprotection and remyelination. CAR‐T cell therapy is a rapidly evolving treatment to combat the neurodegeneration in this autoimmune disease. Systematic search up to March 2026 was conducted across PubMed and Google Scholar. A total of 1046 records were identified, of which 36 were assessed for eligibility and 10 studies were inducted. Quantitative synthesis was not suitable considering the early‐stage nature of the data. Data was extracted methodically into a standardized table format. Results were interpreted descriptively with consideration of study design limitations and consistency of reported outcomes. A total of 32 patients were treated with CAR‐T cell therapy. CRS was the most frequently reported adverse event, occurring in 15 of 24 patients with reported multiple sclerosis‐specific CRS status (62.5%). ICANS was suspected in one patient (1/26, 3.8%). EDSS improvement was reported in 8 of 12 evaluable patients (66.7%). Peripheral B‐cell depletion was consistently reported across evaluated cohorts, including complete depletion in all four patients in the BreakFree‐2 cohort. Evidence of CNS penetration was reported in 13 patients across four cohorts. Current targets for CAR‐T cell therapy include CD‐19 and BCMA. All studies showed an admissible safety profile, encouraging further exploration of this therapy. Favorable clinical outcomes suggest possibility of combating neurodegeneration. Peripheral B‐cell depletion implies possible chances of immune reconstitution. However, longer follow up periods are required to note long term effects and efficacy. All the studies were case reports or Phase 1 trials, further investigation is needed to fully understand and implement the usage of CAR‐T therapy in MS.