Year: 2026
Type: conference-abstract
Abstract: Background Gamma delta (γδ) T cells are a distinct lymphocyte subset with both innate and adaptive immune functions. Unlike conventional αβ T cells, γδ T cells recognize antigens independently of MHC, enabling detection of stress-induced ligands commonly expressed on tumor cells. This makes them particularly attractive for cancer immunotherapy, especially in tumors that evade immune surveillance through MHC downregulation. Engineering γδ T cells with chimeric antigen receptors (CARs) combines their natural tumor recognition with antigen specificity. Compared to αβ CAR T cells, γδ CAR T cells offer advantages including reduced graft-versus-host disease risk, suitability for allogeneic ‘off-the-shelf’ use, and improved solid tumor infiltration. Continued optimization of CAR design is required to maximize their therapeutic potential.Methods T cells from healthy donors were isolated and enriched for γδ T cells via αβ T cell depletion. Cells were activated and transduced with lentiviral CAR constructs, followed by expansion over two weeks. Donor-matched αβ CAR T cells were generated in parallel for direct comparison. CAR expression was confirmed by flow cytometry.Functional activity was assessed with CD107a degranulation assays, bioluminescence-based cytotoxicity assays using luciferase-expressing NALM-6 target cells, and cytokine secretion (IFN-γ, TNF) following co-culture.In vivo efficacy was evaluated in NXG mice injected with NALM-6_luc cells. Mice received IL-15 supplementation every 3–4 days. Tumor progression was monitored by longitudinal bioluminescence imaging (IVIS system), comparing γδ and αβ CAR T cell activity.Results Highly pure γδ and αβ CAR T cell populations with uniform CAR expression were generated. Both cell types showed comparable degranulation upon target engagement. However, αβ CAR T cells demonstrated slower cytotoxic killing kinetics but produced higher cytokine levels.Modification of CAR constructs with the CD3ε cytoplasmic domain resulted in slightly reduced early cytotoxicity, accompanied by decreased cytokine secretion.The NALM-6 xenograft model provided robust tumor engraftment and consistent evaluation conditions. In vivo, αβ CAR T cells exhibited superior antitumor efficacy compared to γδ CAR T cells.Conclusions While αβ CAR T cells demonstrated stronger in vivo efficacy, γδ CAR T cells retain important advantages, including potential for allogeneic use and improved tumor targeting. Functional differences highlight the need for further optimization of CAR signaling domains in γδ T cells. These findings support continued development of γδ CAR T therapies as a promising alternative platform for cancer treatment.
Institutions: Reaction Biology (Germany), University of Freiburg
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225194716