Enrichment of CD7+CXCR3+ CAR T cells in infusion products is associated with durable remission in relapsed or refractory diffuse large B-cell lymphomaBartolini, Trueb, Daoudlarian
et alAnn Oncol (2025)
Abstract: Chimeric antigen receptor (CAR) T-cell therapy is the standard of care for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, more than half of patients fail to achieve durable remission. Identifying predictive biomarkers within the CAR T-cell infusion product (IP) may guide strategies to improve clinical outcomes.This single-center observational study conducted at Lausanne University Hospital (CHUV), Switzerland, analyzed IPs from 13 patients with R/R DLBCL who underwent standard-of-care CAR T-cell therapy. A 39-marker mass cytometry panel was used to compare phenotypic and functional markers between long-term responders (R) and non-responders (NR). Unsupervised and supervised analytic approaches were applied to IP data, and longitudinal peripheral blood samples were collected over 30 days post-infusion to track CAR T-cell subpopulation dynamics.At a median follow-up of 13·5 months, median progression-free survival (PFS) was 13·3 months (95% CI 9·7-24·3) in R (n=8) versus 3·5 months (95% CI 0·5-5·4) in NR (n=5) (hazard ratio 56·67 [95% CI 7·3-439·3]; p=0·0001). A CD3+CXCR3+CD7+ CAR T-cell subpopulation-found in both CD4+ and CD8+ compartments-was significantly enriched in R. These cells showed increased expression of perforin, granzyme B, and NKG2D (restricted to CD8+ cells). In contrast, NR had a higher frequency of CXCR3+CD7+LAG3+ CAR T-cells. Surface expression of CD3, CD7, CXCR3, and NKG2D were higher in R, whereas LAG3, Ki67, and CD71 were elevated in NR. A predictive cut-off ratio of CD3+CXCR3+CD7+LAG3+CAR+ T-cells <0·83 and CD3+CXCR3+CD7+NKG2D+CAR+ T-cells >1·034 yielded a predictive accuracy of 0·92. Serum CXCL9 and CXCL10 concentrations did not differ between groups.Enrichment of CD7+CXCR3+ CAR T-cells alongside elevated NKG2D expression in R, in contrast to higher LAG3 and CD71 in NR, emerged as potentially robust correlates of therapeutic outcome. Although derived from a small, hypothesis-generating cohort, these findings suggest that targeted analysis of IP composition may inform the development of biomarker-driven strategies to optimize CAR T-cell products and improve the likelihood of durable remission in R/R DLBCL.Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.
CD4+ anti-TGF-β CAR T cells and CD8+ conventional CAR T cells exhibit synergistic antitumor effectsZheng, Qin, Lv
et alCell Rep Med (2025) 6 (3), 102020
Abstract: Transforming growth factor (TGF)-β1 restricts the expansion, survival, and function of CD4+ T cells. Here, we demonstrate that CD4+ but not CD8+ anti-TGF-β CAR T cells (T28zT2 T cells) can suppress tumor growth partly through secreting Granzyme B and interferon (IFN)-γ. TGF-β1-treated CD4+ T28zT2 T cells persist well in peripheral blood and tumors, maintain their mitochondrial form and function, and do not cause in vivo toxicity. They also improve the expansion and persistence of untransduced CD8+ T cells in vivo. Tumor-infiltrating CD4+ T28zT2 T cells are enriched with TCF-1+IL7R+ memory-like T cells, express NKG2D, and downregulate T cell exhaustion markers, including PD-1 and LAG3. Importantly, a combination of CD4+ T28zT2 T cells and CD8+ anti-glypican-3 (GPC3) or anti-mesothelin (MSLN) CAR T cells exhibits augmented antitumor effects in xenografts. These findings suggest that rewiring TGF-β signaling with T28zT2 in CD4+ T cells is a promising strategy for eradicating solid tumors.Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
NKG2D-mediated cytotoxicity of CD4 cytotoxic T cells in multiple myelomaKim, Kwak, Koh
et alBlood (2025)
Abstract: Emerging evidence indicates that CD4+ T cells contribute to antitumor immunity beyond their traditional roles as helpers or regulators. However, the specific subset of CD4+ T cells mediating beneficial outcomes in patients with multiple myeloma remains unclear. Here, we performed single-cell RNA sequencing and T cell receptor sequencing on CD4+ T cells sorted from the bone marrow of patients across the stages of myeloma progression. We identified several distinct states of CD4+ cytotoxic T lymphocytes (CTLs) that were significantly increased and clonally expanded in myeloma patients. CD4+ CTLs displayed transcriptional and phenotypic characteristics indicative of cytotoxicity, demonstrating their ability to directly kill myeloma cells. This cytotoxicity, however, was abrogated by NKG2D blockade. Notably, the abundance of NKG2D+CD4+ CTLs correlated with improved survival in myeloma patients. Our findings suggest that harnessing CD4+ CTLs could lead to novel strategies for enhancing immunotherapy outcomes in multiple myeloma.Copyright © 2025 American Society of Hematology.
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