Стойкость мукосальных клеток CAR-T и провокационное переоснащение в энтеноколитах, связанных с клеточной терапией BCMA CAR-T.
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Kethidi Nikhit, Pothukuchi Saumya, Aleman Adolfo, Charytonowicz Daniel, Kuhn Christina, Wong Thomas, Claytor Jennifer, Canales-Herrerias Pablo, Khoshbakht Samane, Acharya Akanksha, Tankelevich Michael, Thin Tin Htwe, Jha Divya, Ceulemans Matthias, Livanos Alexandra E, Le Berre Catherine, Avigan Zachary M, Fischer Luise, Birkness-Gartman Jacqueline E, Melia Joanna, Jin Yimei, Chen Rachel, Parikh Isha, Mehrotra Meenakshi, Patel Erika, Desai Shriya, Reci Sidorela, Ventura Kedwin, Dutta Rudra Prasad, Gordon Benjamin, Brody Rachel, Cunningham-Rundles Charlotte, Chen Zhihong, Kim-Schulze Seunghee, Dulai Parambir S, Naik Shruti, Houldsworth Jane, Merz Maximilian, Longman Randy S, Zanoni Ivan, Faith Jeremiah, Colombel Jean-Frederic, Siegmund Britta, Atreya Raja, Neurath Markus F, Richard Shambavi, Jagannath Sundar, Martin Jerome C, Meffre Eric, Suarez-Farinas Mayte, Pedrogo David Muniz, Polydorides Alexandros D, Parekh Samir, Mehandru Saurabh
Аннотация
Оригинал публикации
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 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.