Two-stage CD8+ CAR T-cell differentiation in patients with large B-cell lymphoma

Guoshuai Cao, Yifei Hu, Tony Pan, Erting Tang, Nicholas Asby, Thomas Althaus, Jun Wan, Peter A. Riedell, Michael R. Bishop, Justin P. Kline and Jun Huang ()
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Guoshuai Cao: University of Chicago
Yifei Hu: University of Chicago
Tony Pan: University of Chicago
Erting Tang: University of Chicago
Nicholas Asby: University of Chicago
Thomas Althaus: University of Chicago
Jun Wan: Indiana University School of Medicine
Peter A. Riedell: University of Chicago
Michael R. Bishop: University of Chicago
Justin P. Kline: University of Chicago
Jun Huang: University of Chicago

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Advancements in chimeric antigen receptor (CAR) T-cell therapy for treating diffuse large B-cell lymphoma (DLBCL) have been limited by an incomplete understanding of CAR T-cell differentiation in patients. Here, we show via single-cell, multi-modal, and longitudinal analyses, that CD8+ CAR T cells from DLBCL patients successfully treated with axicabtagene ciloleucel undergo two distinct waves of clonal expansion in vivo. The first wave is dominated by an exhausted-like effector memory phenotype during peak expansion (day 8–14). The second wave is dominated by a terminal effector phenotype during the post-peak persistence period (day 21–28). Importantly, the two waves have distinct ontogeny from the infusion product and are biologically uncoupled. Precursors of the first wave exhibit more effector-like signatures, whereas precursors of the second wave exhibit more stem-like signatures. We demonstrate that CAR T-cell expansion and persistence are mediated by clonally, phenotypically, and ontogenically distinct CAR T-cell populations that serve complementary clinical purposes.

Date: 2025
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DOI: 10.1038/s41467-025-59298-w

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