Persistence of mucosal CAR-T cells and inflammatory remodeling in enterocolitis associated with BCMA CAR-T cell...

B cell-targeted therapies are expanding across oncologic and autoimmune indications, yet their consequences for mucosal immunity remain incompletely examined. Here we define the pathophysiology of ciltacabtagene autoleucel chimeric antigen receptor (CAR)-T cell-induced enterocolitis (EC) (CAR-T_EC)-a severe complication of B cell maturation antigen-targeted CAR-T cell therapy in multiple myeloma. Using single-cell transcriptomics, flow cytometry and tissue imaging of intestinal biopsies from patients with CAR-T_EC (n = 10), CAR-T cell-treated controls without EC (n = 7) and healthy volunteers (n = 26), we identify profound depletion of mucosal B cells and plasma cells accompanied by expansion of highly cytotoxic CAR-T cells and inflammatory myeloid, stromal and glial cell remodeling to be associated with CAR-T_EC. Cell-cell communication analyses suggest a compensated mucosal state in CAR-T cell-treated controls, telocyte-driven stromal niche dysfunction as noted in CAR-T_EC. Interferon- and Janus kinase (JAK) and signal transducer and activator of transcription-associated reprogramming was noted across stromal, endothelial and epithelial compartments, supporting JAK inhibition as a rational, mechanism-based therapeutic strategy. Upadacitinib-an oral selective JAK 1 inhibitor-resulted in clinical, endoscopic and histologic improvement in two people with CAR-T_EC. Our findings define CAR-T_EC as a multicompartment syndrome of severe mucosal dysregulation with implications for the emerging field of B cell-targeted therapies.