Silvia Arcangeli; Camilla Bove; Claudia Mezzanotte; Barbara Camisa; Laura Falcone; Francesco Manfredi; Eugenia Bezzecchi; Rita El Khoury; Rossana Norata; Francesca Sanvito; Maurilio Ponzoni; Beatrice Greco; Marta Angiola Moresco; Matteo G. Carrabba; Fabio Ciceri; Chiara Bonini; Attilio Bondanza; Monica Casucci · 2022 · Journal of Clinical Investigation
Paper
Chimeric antigen receptor (CAR) T cell expansion and persistence represent key factors to achieve complete responses and prevent relapses. These features are typical of early memory T cells, which can be highly enriched through optimized manufacturing protocols. Here, we investigated the efficacy and safety profiles of CAR T cell products generated from preselected naive/stem memory T cells (TN/SCM), as compared with unselected T cells (TBULK). Notwithstanding their reduced effector signature in vitro, limiting CAR TN/SCM doses showed superior antitumor activity and the unique ability to counteract leukemia rechallenge in hematopoietic stem/precursor cell-humanized mice, featuring increased expansion rates and persistence together with an ameliorated exhaustion and memory phenotype. Most relevantly, CAR TN/SCM proved to be intrinsically less prone to inducing severe cytokine release syndrome, independently of the costimulatory endodomain employed. This safer profile was associated with milder T cell activation, which translated into reduced monocyte activation and cytokine release. These data suggest that CAR TN/SCM are endowed with a wider therapeutic index compared with CAR TBULK.
Analysis
Manufacturing CAR T cells from naive/stem memory T cells improves antitumor activity and persistence while reducing cytokine release syndrome compared to unselected T cells.
Discovery
Estelle Baulu; Célia Gardet; Nicolas Chuvin; Stéphane Depil
Robert C. Sterner; Rosalie M. Sterner; Rosalie M. Sterner; Rosalie M. Sterner
Matteo Morotti; Ashwag Albukhari; Abdulkhaliq Alsaadi; Mara Artibani; James D. Brenton; Stuart M. Curbishley; Tao Dong; Michael L. Dustin; Zhiyuan Hu; Nicholas McGranahan; Martin L. Miller; Laura Santana-Gonzalez; Leonard W. Seymour; Tingyan Shi; Peter Van Loo; Christopher Yau; Helen White; Nina Wietek; David N. Church; David C. Wedge; Ahmed A. Ahmed
Yongxian Hu; Yali Zhou; Mingming Zhang; Wengang Ge; Yi Li; Li Yang; Guoqing Wei; Lu Han; Hao Wang; Shuhui Yu; Yi Chen; Yanbin Wang; Xiaohong He; Xingwang Zhang; Ming Gao; Jingjing Yang; Xiuju Li; Jiangtao Ren; He Huang
Joe-Marc Chauvin; Hassane M Zarour
Michael Wang; Javier Muñoz; André Goy; Frederick L. Locke; Caron A. Jacobson; Brian T. Hill; John M. Timmerman; Houston Holmes; Samantha Jaglowski; Ian W. Flinn; Peter A. McSweeney; David B. Miklos; John M. Pagel; Marie José Kersten; Nöel Milpied; Henry C. Fung; Max S. Topp; Roch Houot; Amer Beitinjaneh; Weimin Peng; Lianqing Zheng; John M. Rossi; Rajul K. Jain; Arati V. Rao; Patrick M. Reagan
Source record