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

B cell-targeted therapies are expanding across oncologic and autoimmune indications, yet their consequences for immunity remain incompletely examined. Here, we define the mucosal pathophysiology of ciltacabtagene autoleucel CAR-T cell-induced enterocolitis (CAR-TEC), a severe complication of B cell maturation antigen (BCMA)-targeted CAR-T cell therapy in multiple myeloma. Using single-cell transcriptomics, flow cytometry, and tissue imaging of intestinal biopsies from patients with CAR-TEC (n=10), CAR-T cell treated controls (CAR-TCTRL) without enterocolitis (n=7), and healthy volunteers (n=26), we identify profound depletion of mucosal B cells and plasma cells (PCs) accompanied by expansion of highly cytotoxic CAR-T cells and inflammatory myeloid, stromal, and glial cell remodeling to be associated with CAR-TEC. Cell-cell communication analyses suggest a compensated mucosal state in CAR-TCTRL, while telocyte-driven stromal niche dysfunction was noted in CAR-TEC. Interferon and JAK-STAT-associated reprogramming was noted across stromal, endothelial, and epithelial compartments, supporting JAK inhibition as a rational, mechanism-based therapeutic strategy. Upadacitinib, an oral selective JAK1 inhibitor resulted in clinical, endoscopic and histologic improvement in 2 individuals with CAR-TEC. Our findings define CAR-TEC as a multi-compartment syndrome of severe mucosal dysregulation with implications for the emerging field of B cell-targeted therapies.