| Neuroscience/ Translational neurology  

CAR T cell therapy in autoimmune neurological disorders

CAR‑T therapy, originally developed for oncology, is now emerging as a potential treatment modality in neuroimmunology. By engineering patients’ T cells to express chimeric antigen receptors against B‑cell targets such as CD19 or BCMA, this approach enables selective depletion of pathogenic lymphocytes in an MHC‑independent manner. The first multicenter trial of RNA‑based CAR‑T therapy in myasthenia gravis from 2023 demonstrated acceptable safety and clinically meaningful, sustained improvements. Ongoing studies in multiple B‑cell–mediated neurological disorders will clarify whether CAR‑T therapy can provide durable disease control and reshape treatment strategies in autoimmune neurology.

CAR-T therapy, or Chimeric Antigen Receptor T cell therapy, is a form of immunotherapy in which patients’ T cells are engineered to express synthetic receptors known as CARs. This engineering allows the immune system to specifically target disease-associated antigens, enabling it to attack unwanted cells, such as cancer cells or autoreactive lymphocytes. The mechanisms underlying CAR-T therapy were first elucidated by the immunologist Zelig Eshhar and his team in 1989 (1). They discovered that the variable regions of antibodies could be fused with T cell receptor domains to create a chimeric receptor, which enabled T cells to target antigens in an MHC-independent manner.

However, it took several years before this treatment became available for human use. In 2014, Maude and colleagues published the first study examining CAR-T therapy in patients with acute lymphoblastic leukemia (ALL) (2), reporting an overall remission rate of 81%. As conventional CAR-T therapy carries the potential for severe side effects, such as major cytokine release syndrome and neurotoxicity, it was not until 2023 that the first multicenter study utilizing CAR-T therapy in neurology was published (3). In this study, RNA-based CAR-T therapy was applied to patients with myasthenia gravis, demonstrating a reduction in disease severity and enabling the discontinuation of intravenous immunoglobulin in responsive patients, with improvements sustained for up to nine months.

Currently, several studies are underway to assess the efficacy of CAR-T therapy for autoimmune neurological disorders, particularly those driven by pathogenic B cells, including multiple sclerosis (MS), stiff person syndrome, neuromyelitis optica spectrum disorder, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis. At present, CAR-T therapy in neurology is primarily employed to eliminate specific harmful B cells from the body, utilizing anti-CD19 or anti-BCMA CARs. The objective is to eradicate the cells responsible for the disease and support long-term health in patients. It will be interesting to observe the evolving role of this therapy in the treatment of autoimmune neurological disorders in the future.

Key Points:

  • CAR‑T therapy reprograms patients’ T cells with chimeric antigen receptors, enabling MHC‑independent targeting of disease‑associated antigens such as CD19 or BCMA on B cells.
  • After its initial development in the late 1980s and landmark success in hematological malignancies, CAR‑T therapy is now entering neurology, with the first multicenter trial in myasthenia gravis published in 2023.
  • Early data from RNA‑based CAR‑T therapy in myasthenia gravis show reduced disease severity and discontinuation of IVIg in responders, with effects maintained for several months.
  • Multiple trials are underway in B‑cell–driven autoimmune neurological diseases, including MS, stiff‑person syndrome, NMOSD, CIDP and myasthenia gravis.

References:

  1. Eshhar, Z., Waks, T., Gross, G., & Schindler, D. G. (1993). Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proceedings of the National Academy of Sciences, 90(2), 720-724.
  2. Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., ... & Grupp, S. A. (2014). Chimeric antigen receptor T cells for sustained remissions in leukemia. New England Journal of Medicine, 371(16), 1507-1517.
  3. Granit, V., Benatar, M., Kurtoglu, M., Miljković, M. D., Chahin, N., Sahagian, G., ... & Jewell, C. M. (2023). Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study. The Lancet Neurology, 22(7), 578-590.

Publish on behalf of the Coordinating Panel on Neuroscience/ Translational Neurology

Back