Durable response to CAR T is associated with elevated activation and clonotypic expansion of the cytotoxic native T cell repertoire
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.
Authors
- Brodie Miles (ORCID: https://orcid.org/0000-0002-5670-4432)
- Dimitra Karagkouni (ORCID: https://orcid.org/0009-0007-3961-3399)
- Mike Mattie (ORCID: https://orcid.org/0000-0003-0868-3865)
- Eleni Kanata (ORCID: https://orcid.org/0009-0009-2828-2226)
- Gayatri Tiwari
- Ioannis S. Vlachos (ORCID: https://orcid.org/0000-0002-8849-808X)
- Kathrine S Rallis (ORCID: https://orcid.org/0000-0003-1011-3220)
- David Avigan (ORCID: https://orcid.org/0000-0003-4624-6017)
- Jacalyn Rosenblatt (ORCID: https://orcid.org/0000-0001-5582-8161)
- Jenny Kim (ORCID: https://orcid.org/0009-0008-6816-1499)
- Yered Pita-Juárez (ORCID: https://orcid.org/0000-0001-6992-252X)
- Georges Chedid (ORCID: https://orcid.org/0000-0002-5708-2954)
- Giulia Cheloni (ORCID: https://orcid.org/0000-0002-7682-3826)
- Zachary M. Avigan (ORCID: https://orcid.org/0000-0003-1208-9260)
- Isabella Saldarriaga
- Daniela Torres (ORCID: https://orcid.org/0000-0003-3452-7081)
- Jessica J. Liegel (ORCID: https://orcid.org/0009-0007-8014-706X)
Institutions
- Broad Institute (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1038/s41467-025-59904-x
- Citations
- 8
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 8.36
Funders
- Gilead Sciences
- Beth Israel Deaconess Medical Center