Commentary - Comparative efficacy and safety of PSCA CAR-engineered Vδ1 γδ T cells for immunotherapy of pancreatic cancer

Sep 23, 2026

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Adoptive transfer of unmodified γδ T cells has shown limited clinical benefit, driving a shift toward CAR engineering to improve activation, persistence, and tumor specificity. γδ CAR-T is framed as promising for HLA-independent targeting and innate-like cytotoxicity. Evidence from αβ CAR-T trials suggests γδ CART persistence for months to years, supporting potential long-term immune surveillance. Comparative benchmarking among Vδ1, Vγ9Vδ2, and αβ subsets emphasizes distinct transcriptional programs and supports subset-specific optimization, including preclinical proof-of-concept before addressing solid-tumor barriers.

LanguageEnglish

CategoryResearch & Report

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Pages6

Reading Time15 min

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ABSTRACT

CAR engineering shift in γδ T-cell therapy

Persistence and immune surveillance rationale

Subset differences: Vδ1 vs Vγ9Vδ2 vs αβ

Manufacturing implications and optimization needs

Open access Commentary Commentary on “Comparative efficacy and safety of PSCA CAR-engineered Vδ1 γδ T cells for immunotherapy of pancreatic cancer” Dorine A de Bont,1 Trudy Straetemans,1,2 Zsolt Sebestyén,1 Jurgen Kuball 1,2 To cite: de Bont DA, Straetemans T, Sebestyén Z, et al. Commentary on“Comparative efficacy and safety of PSCA CARengineered Vδ1 γδ T cells for immunotherapy of pancreatic cancer”. Journal for ImmunoTherapy of Cancer 2026;14:e014199 . doi:10 . 1136/ jitc-2025-014199 ► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/10.1136/](https://doi.org/10.1136/)[ ](https://doi.org/10.1136/)[jitc-2025-014199](jitc-2025-014199)) . Accepted 01 February 2026 © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. 1Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands 2Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands Correspondence to Dr Jurgen Kuball; [J.H.E.Kuball@umcutrecht.nl](J.H.E.Kuball@umcutrecht.nl) ABSTRACT Adoptive transfer of unmodified γδ T cells has shown limited clinical benefit, prompting a shift toward chimeric antigen receptor (CAR) engineering to enhance activation, persistence, and tumor specificity. CAR technology positions γδ T cells as promising carriers due to their innate-like cytotoxicity and HLA-independent recognition. Evidence from αβ CAR T-cell trials indicates that γδ CART cells can persist for months to years post-infusion, suggesting their potential contribution to long-term immune surveillance against cancer. Among γδ subsets, Vγ9Vδ2 T cells dominate peripheral blood and have been preferentially used for CAR engineering. Recent advances, however, enable the expansion of Vδ1 T cells, known for their tissue residency and resistance to exhaustion. Ina key comparative study, Li etal benchmarked PSCAtargeted CARs in Vδ1, Vγ9Vδ2, and αβ T cells, showing similar short-term tumor control but distinct transcriptional and phenotypic programs. These findings highlight the need for subset-specific optimization of γδ CAR-T therapies. Early studies in hematologic malignancies could provide a practical proof of concept, before tackling the additional challenges of solid tumors. Such focused development may be essential to advance the γδ CAR-T field amid tightening industry investment. Given the limited clinical activity observed with adoptively transferred natural γδ T cells, the field has shifted toward engineering strategies that provide both additional activation signals and tumor antigen specificity through CARs.1 The introduction of CAR technology has emerged as a promising strategy to enhance γδ T-cell potency and redirect their activity toward tumor cells, thereby transforming them into highly effective antitumor effectors.1 2 Interestingly, accumulating evidence suggests that γδ T cells may contribute to long-term CAR-T cell persistence when primary αβ T cells are engineered without prior selection for CD4+ or CD8+ subsets. Given that peripheral blood contains 1–10% γδ T cells, predominantly of the Vγ9Vδ2 subtype, these cells become transduced during manufacturing and potentially persist after infusion. Indeed, two clinical studies of conventional αβ T cell-derived CAR-T products have reported γδ CAR-T cells persisting from months to years post-infusion. In one anti-CD19 CAR-T trial, γδ CAR-T cells were detected both early (2.5 months) and at long-term follow-up (7.2 years), expressing cytotoxic markers such as granzyme B, CD57, and T-bet, consistent with sustained effector function.3 A similar finding was reported in another pediatric anti-CD19 CAR-T study, where γδ CAR-T cells were observed at early post-infusion time points in a subset of patients.4 Although the clinical relevance of these populations re

FAQs

Why has γδ CAR engineering become important for pancreatic cancer immunotherapy?

Limited benefit from unmodified γδ T cell transfer has led to CAR engineering strategies that enhance activation, persistence, and tumor antigen specificity for stronger antitumor activity.

What biological features make γδ T cells attractive CAR-T carriers?

γδ T cells can provide innate-like cytotoxicity and HLA-independent antigen recognition, which supports an “off-the-shelf” therapeutic platform, while also raising considerations such as possible allo-HLA reactivity.

How do Vδ1 and Vγ9Vδ2 γδ subsets differ in the context of CAR-T therapy?

A key comparative study reported similar short-term tumor control across subsets, but distinct transcriptional and phenotypic programs, highlighting the need for subset-specific CAR-T optimization.

Sep 23, 2026

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