[Pubmed] B cell lineage reconstitution underlies CAR-T cell therapeutic efficacy in patients with refractory myasthenia

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EMBO Mol Med. 2024 Feb 26. doi: 10.1038/s44321-024-00043-z. Online ahead of print.

ABSTRACT

B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8+ Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.

PMID:38409527 | DOI:10.1038/s44321-024-00043-z


Source: https://pubmed.ncbi.nlm.nih.gov/3840952 ... t9+e462414