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Common Trajectories of Highly Effective CD19-Specific CAR T Cells Identified by Endogenous T-cell Receptor Lineages

2022; American Association for Cancer Research; Volume: 12; Issue: 9 Linguagem: Inglês

10.1158/2159-8290.cd-21-1508

2159-8290

Taylor L. Wilson, Hyunjin Kim, Ching‐Heng Chou, Deanna Langfitt, Robert C. Mettelman, Anastasia A. Minervina, E. Kaitlynn Allen, Jean‐Yves Métais, Mikhail V. Pogorelyy, Janice M. Riberdy, Mireya Paulina Velasquez, Pratibha Kottapalli, Sanchit Trivedi, Scott R. Olsen, Timothy Lockey, Catherine Willis, Michael M. Meagher, Brandon M. Triplett, Aimee C. Talleur, Stephen Gottschalk, Jeremy Chase Crawford, Paul G. Thomas,

Silicon Carbide Semiconductor Technologies

Current chimeric antigen receptor-modified (CAR) T-cell products are evaluated in bulk, without assessing functional heterogeneity. We therefore generated a comprehensive single-cell gene expression and T-cell receptor (TCR) sequencing data set using pre- and postinfusion CD19-CAR T cells from blood and bone marrow samples of pediatric patients with B-cell acute lymphoblastic leukemia. We identified cytotoxic postinfusion cells with identical TCRs to a subset of preinfusion CAR T cells. These effector precursor cells exhibited a unique transcriptional profile compared with other preinfusion cells, corresponding to an unexpected surface phenotype (TIGIT+, CD62Llo, CD27-). Upon stimulation, these cells showed functional superiority and decreased expression of the exhaustion-associated transcription factor TOX. Collectively, these results demonstrate diverse effector potentials within preinfusion CAR T-cell products, which can be exploited for therapeutic applications. Furthermore, we provide an integrative experimental and analytic framework for elucidating the mechanisms underlying effector development in CAR T-cell products.