Chimeric antigen receptor T-cell therapy for autoimmune diseases of the central nervous system: a systematic literature review

Abstract

Importance: B-cell-targeting monoclonal antibodies have demonstrated safety and efficacy in multiple sclerosis or anti-aquaporin-4 IgG positive neuromyelitis optica spectrum disorder. However, these therapies do not facilitate drug-free remission, which may become possible with cell-based therapies, including chimeric antigen receptor (CAR) T cells. CAR T-cell therapy holds promise for addressing other antibody-mediated CNS disorders, e.g., MOG-associated disease or autoimmune encephalitis.

Objective: To provide an overview of the current clinical knowledge on CAR T-cell therapy in central nervous system autoimmunity.

Evidence review: We searched PubMed, Embase, Google Scholar, PsycINFO, and clinicaltrials.gov using the terms 'CAR T cell' and 'multiple sclerosis/MS' or 'neuromyelitis optica/spectrum diseases/NMOSD' or 'MOG-associated disease/MOGAD 'or' autoimmune encephalitis' or 'neuroimmunology'.

Findings: An ongoing phase I clinical trial has indicated the safety and benefits of anti-BCMA CAR T cells in 12 patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder. Case reports involving two individuals with progressive multiple sclerosis and one patient with stiff-person syndrome demonstrated a manageable safety profile following treatment with anti-CD19 CAR T cells. Recruitment has commenced for two larger studies in MS, and a phase I open-label basket study is underway to evaluate BCMA-directed CAR T cells in various antibody-associated inflammatory diseases, including MOG-associated disease. Preclinical research on NMDA receptor antibody autoimmune encephalitis treated with chimeric autoantibody receptor T cells generated promising data.

Conclusions and relevance: There is minimal evidence of the benefits of CAR T-cell therapy in individuals with central nervous system-directed autoimmunity. Nevertheless, multicenter controlled clinical trials with a manageable safety profile appear feasible and are warranted due to very promising case experiences.

Keywords: Antibody-mediated CNS disorders; CAR T-cell therapy; Central nervous system autoimmunity; Multiple sclerosis; NMOSD.

Fig. 1

A CAR T-cell structure: first-generation CARs contain an intracellular signaling domain of CD3 zeta chain alone; second-generation CARs includes a single co-stimulatory domain (CD28 or 4-1BB); third-generation CARs combine two of the co-stimulatory domains; fourth generation CARs with transgene to express cytokines [48]; bispecific/dual-CAR T cells: CAR T cells recognizing two targets simultaneously on target cells; split signal CARs: The two split structures of the CAR-T cell are assembled and activated in the presence of a specific particular molecule. B CAR T cells—the application in clinical practice

Fig. 2

Mechanism of action of three B-cell depleting therapies. mAb monoclonal antibody, CAR T chimeric antigen receptor T cell, CAAR T chimeric autoantibody receptor T cell, MuSK muscle-specific kinase