Published on July 23, 2025
Durable response to CAR T is associated with elevated activation and clonotypic expansion of the cytotoxic native T cell repertoire
by Alex Kadhim
Researchers at Beth Israel Deaconess Medical Center and collaborators have found that durable remission following CART-cell therapy (axicabtagene ciloleucel; Axi-cel) in patients with relapsed/refractory large B-cell lymphoma (LBCL) is primarily associated with activation and clonotypic expansion of native cytotoxic T cells, rather than persistence or abundance of the infused CAR T cells themselves. This discovery emphasizes the critical role of the patient’s own immune system in maintaining long-term remission, suggesting the need for therapeutic approaches that enhance native T cell responses to improve CAR T outcomes.
The rationale behind this study stemmed from the observation that although CAR T cells rapidly decline after infusion, many patients still maintain durable remission. Researchers hypothesized that CAR T-mediated inflammation and tumor lysis might activate native T cells, driving an adaptive immune response that prevents relapse. Using longitudinal single-cell RNA and T-cell receptor sequencing, the team examined peripheral blood samples from 32 LBCL patients treated with Axi-cel in the ZUMA-1 clinical trial (NCT02348216). Samples were collected at leukapheresis (baseline), 4 weeks, 6 months, and 12 months post infusion. The patients were categorized based on clinical outcomes: long-term responders (>1-year remission), early relapse (<6 months), and non-responders (no remission).
Results indicated substantial differences between these patient groups. At 4 weeks post-infusion, long-term responders demonstrated significantly elevated levels of non-CAR cytotoxic CD8 and CD4 T cells expressing markers of enhanced cytotoxicity (e.g.,granzyme B, perforin, NKG7; FDR <2.2×10⁻¹⁶), pro-inflammatory cytokines (e.g., IFN-γ, IL-21, IL-12; FDR<0.01), and proliferative potential. Additionally, durable responders exhibited distinct clonotypic expansion patterns of native T-cell receptors, reflecting potential activation against tumor-specific antigens. This clonotypic expansion at 4 weeks post-infusion effectively predicted long-term remission (AUC=0.89). Conversely, early relapse patients displayed increased regulatory T cells, impaired NK cell function (p<0.01), and higher inflammatory monocyte populations (FDR<0.05), creating an immunosuppressive environment unfavorable to sustaining remission. This study underscores that boosting native T cell responses and their clonotypic expansion could be crucial for maximizing CAR T-cell therapeutic efficacy.
Reference:
Cheloni G, Karagkouni D, Pita-Juarez Y, et al. Durable response to CAR T is associated with elevated activation and clonotypic expansion of the cytotoxic native T cell repertoire. Nat Commun. 2025;16(1):4819. Published 2025 May 23.
http://doi.org/10.1038/s41467-025-59904-x
![]()