Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells

Cell. 2023 Nov 9;186(23):5084-5097.e18. doi: 10.1016/j.cell.2023.10.001. Epub 2023 Nov 1.

Abstract

Anti-NMDA receptor (NMDAR) autoantibodies cause NMDAR encephalitis, the most common autoimmune encephalitis, leading to psychosis, seizures, and autonomic dysfunction. Current treatments comprise broad immunosuppression or non-selective antibody removal. We developed NMDAR-specific chimeric autoantibody receptor (NMDAR-CAAR) T cells to selectively eliminate anti-NMDAR B cells and disease-causing autoantibodies. NMDAR-CAARs consist of an extracellular multi-subunit NMDAR autoantigen fused to intracellular 4-1BB/CD3ζ domains. NMDAR-CAAR T cells recognize a large panel of human patient-derived autoantibodies, release effector molecules, proliferate, and selectively kill antigen-specific target cell lines even in the presence of high autoantibody concentrations. In a passive transfer mouse model, NMDAR-CAAR T cells led to depletion of an anti-NMDAR B cell line and sustained reduction of autoantibody levels without notable off-target toxicity. Treatment of patients may reduce side effects, prevent relapses, and improve long-term prognosis. Our preclinical work paves the way for CAAR T cell phase I/II trials in NMDAR encephalitis and further autoantibody-mediated diseases.

Keywords: CAAR T cell; NMDA receptor encephalitis; T cells; autoimmune encephalitis; autoimmunity; cell therapy; chimeric autoantibody receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies* / metabolism
  • Autoimmune Diseases
  • Disease Models, Animal
  • Encephalitis* / metabolism
  • Encephalitis* / therapy
  • Humans
  • Mice
  • Receptors, N-Methyl-D-Aspartate
  • T-Lymphocytes*

Substances

  • Autoantibodies
  • Receptors, N-Methyl-D-Aspartate