Nikhit Kethidi, Saumya Pothukuchi, Adolfo Aleman, Daniel Charytonowicz, Christina Kuhn, Thomas Wong, Jennifer Claytor, Pablo Canales-Herrerias, Samane Khoshbakht, Akanksha Acharya, Michael Tankelevich, Tin Htwe Thin, Divya Jha, Matthias Ceulemans, Alexandra E Livanos, Catherine Le Berre, Zachary M Avigan, Luise Fischer, Jacqueline E Birkness-Gartman, Joanna Melia, Yimei Jin, Rachel Chen, Isha Parikh, Meenakshi Mehrotra, Erika Patel, Shriya Desai, Sidorela Reci, Kedwin Ventura, Rudra Prasad Dutta, Benjamin Gordon, Rachel Brody, Charlotte Cunningham-Rundles, Zhihong Chen, Seunghee Kim-Schulze, Parambir S Dulai, Shruti Naik, Jane Houldsworth, Maximilian Merz, Randy S Longman, Ivan Zanoni, Jeremiah Faith, Jean-Frederic Colombel, Britta Siegmund, Raja Atreya, Markus F Neurath, Shambavi Richard, Sundar Jagannath, Jerome C Martin, Eric Meffre, Mayte Suarez-Farinas, David Muniz Pedrogo, Alexandros D Polydorides, Samir Parekh, Saurabh Mehandru
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-TEC)-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-TEC (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-TEC. Cell-cell communication analyses suggest a compensated mucosal state in CAR-T cell-treated controls, telocyte-driven stromal niche dysfunction as noted in CAR-TEC. 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-TEC. Our findings define CAR-TEC as a multicompartment syndrome of severe mucosal dysregulation with implications for the emerging field of B cell-targeted therapies.