Common trajectories of highly effective CD19-specific CAR T cells identified by endogenous T cell receptor lineages

Taylor L. Wilson, Hyunjin Kim, Ching-Heng Chou, Deanna Langfitt, E. Kaitlynn Allen, Jean-Yves Métais, Mikhail V. Pogorelyy, 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
2021 · doi:10.1101/2021.12.05.21266287
preprint OA: closed CC-BY-NC-ND-4.0
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Abstract

Current chimeric antigen receptor-modified (CAR) T cell therapy products are evaluated in bulk, without assessment of the possible heterogeneity in effector potential between cells. Conceivably, only a subset of the pre-infusion product differentiates into optimal effectors. We generated a comprehensive single-cell gene expression and T cell receptor (TCR) sequencing dataset using both pre- and post-infusion CD19-CAR T cells from peripheral blood and bone marrow of pediatric patients with B cell acute lymphoblastic leukemia (B-ALL). We identified potent effector post-infusion cells with identical TCRs to a subset of pre-infusion CAR T cells. Effector precursor CAR T cells exhibited a unique transcriptional profile compared to other pre-infusion cells, and the number of effector precursor cells infused correlated with peak CAR T cell expansion. Additionally, we identified an unexpected cell surface phenotype (TIGIT+, CD62L lo , CD27-), conventionally associated with inhibiting effective T cell responses, that we used to successfully enrich for subsequent effector potential. Collectively, these results demonstrate that highly diverse effector potentials are present among cells in pre-infusion cell products, which can be exploited for diagnostic and therapeutic applications. Furthermore, we provide an integrative experimental and analytical framework for elucidating the biological mechanisms underlying effector development in other CAR T cell therapy products.

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License: CC-BY-NC-ND-4.0