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

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. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease group with CAR T cells offering therapeutic success in otherwise hard-to-treat cases. Here, authors study the in vivo expansion and persistence of CAR T cells in the peripheral blood of successfully treated DLBCL patients, demonstrating that two different CD8+ precursor phenotypes in the initial cell product give rise to two independent waves of clonally expanded CAR T cells with distinct phenotypes in peripheral blood.