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

NMDAR encephalitis is characterized by the presence of specific autoantibodies that specifically target the NMDAR channel and have been shown to be pathogenic in various in vitro and in vivo models. Reincke et Al. developed a CAAR NMDAR which permit to eliminate selective B cells that produce NMDAR autoantibodies. In detail, they developed a CAAR NMDAR by fusing an extracellular multi-subunit NMDAR (N1ATD and N2B ATD) autoantigen with the CD8 zipper and an intracellular 4-1BB/CD3z signaling domain demonstrating that:

  • NMDAR-CAAR T cells selectively target autoreactive NMDAR-cells and can recognized multiple monoclonal antibodies that react with different NMDAR epitopes
  • NMDAR-CAAR T cells can proliferate and deplete the NMDAR-producing cell lineage even in the presence of high concentrations of autoantibodies
  • NMDAR-CAAR T cells can reach in the central nervous system reducing the antibody levels in the brain
  • NMDAR-CAAR T cells kill target NMDAR producing cells in vivo without signs of therapy-induced toxicity

The major limitation of the study concerns the characteristics of the animal model used with a passive transfer of autoantibody-producing B-cells because it does not recapitulate the NMDAR clinical phenotype and does not allow to investigate the efficacy of NMDAR-CAAR T in vivo on autoantibody-mediated symptoms. However, this work is extremely relevant because the increasing knowledge of CAART therapy in autoantibody-mediated diseases makes this therapy ever closer to being a new arrow to our bow for the treatment of neurological disorders mediated by neuroglial autoantibodies.