Durable response to CAR T is associated with elevated activation and clonotypic expansion of the cytotoxic native T cell repertoire

Giulia Cheloni, Dimitra Karagkouni, Yered Pita-Juarez, Daniela Torres, Eleni Kanata, Jessica Liegel, Zachary Avigan, Isabella Saldarriaga, Georges Chedid, Kathrine Rallis, Brodie Miles, Gayatri Tiwari, Jenny Kim, Mike Mattie, Jacalyn Rosenblatt, Ioannis S. Vlachos and David Avigan ()
Additional contact information
Giulia Cheloni: Beth Israel Deaconess Medical Center
Dimitra Karagkouni: Beth Israel Deaconess Medical Center
Yered Pita-Juarez: Beth Israel Deaconess Medical Center
Daniela Torres: Beth Israel Deaconess Medical Center
Eleni Kanata: Beth Israel Deaconess Medical Center
Jessica Liegel: Beth Israel Deaconess Medical Center
Zachary Avigan: Beth Israel Deaconess Medical Center
Isabella Saldarriaga: Beth Israel Deaconess Medical Center
Georges Chedid: Beth Israel Deaconess Medical Center
Kathrine Rallis: Beth Israel Deaconess Medical Center
Brodie Miles: a Gilead Company
Gayatri Tiwari: a Gilead Company
Jenny Kim: a Gilead Company
Mike Mattie: a Gilead Company
Jacalyn Rosenblatt: Beth Israel Deaconess Medical Center
Ioannis S. Vlachos: Beth Israel Deaconess Medical Center
David Avigan: Beth Israel Deaconess Medical Center

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

Abstract: Abstract While Chimeric Antigen Receptor (CAR) T cell therapy may result in durable remissions in recurrent large B cell lymphoma, persistence is limited and the mechanisms underlying long-term response are not fully elucidated. Using longitudinal single-cell immunoprofiling, here we compare the immune landscape in durable remission versus early relapse patients following CD19 CAR T cell infusion in the NCT02348216 (ZUMA-1) trial. Four weeks post-infusion, both cohorts demonstrate low circulating CAR T cells. We observe that long-term remission is associated with elevated native cytotoxic and proinflammatory effector cells, and post-infusion clonotypic expansion of effector memory T cells. Conversely, early relapse is associated with impaired NK cell cytotoxicity and elevated immunoregulatory cells, potentially dampening native T cell activation. Thus, we suggest that durable remission to CAR T is associated with a distinct T cell signature and pattern of clonotypic expansion within the native T cell compartment post-therapy, consistent with their contribution to the maintenance of response.

Date: 2025
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DOI: 10.1038/s41467-025-59904-x

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