CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome
Silvia Arcangeli, Camilla Bove, Claudia Mezzanotte, Barbara Camisa, Laura Falcone, Francesco Manfredi, Eugenia Bezzecchi, El Khoury, Rita, Rossana Norata, Francesca Sanvito, Maurilio Ponzoni, Béatrice Gréco, Marta Angiola Moresco, Matteo Giovanni Carrabba, Fabio Ciceri, Chiara Bonini, Attilio Bondanza, Monica Casucci
Abstract
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 T BULK.