Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer

TLDR

Vγ9Vδ2 T cells are promising, HLA‑independent tumor‑immune effectors suitable for allogeneic therapy. The study aimed to optimize in‑vitro expansion of allogeneic Vγ9Vδ2 T cells and demonstrate their clinical safety and efficacy in adoptive immunotherapy. A novel donor‑derived expansion protocol was developed, validated in a humanized mouse model, and the resulting cells were adoptively transferred into late‑stage liver and lung cancer patients. Expanded cells showed superior proliferation, differentiation, and tumor‑cell killing in vitro and in mice, and a phase‑I trial of 132 patients (414 infusions) confirmed safety and revealed markedly prolonged survival in 8 liver and 10 lung patients receiving ≥5 infusions.

Abstract

Abstract Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy. Due to their HLA-independent mode of action, allogeneic Vγ9Vδ2 T cells can be considered for clinical application. To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy, the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized, and clinical safety and efficacy also need to be proven. Therefore, we developed a novel formula to improve the expansion of peripheral γδ T cells from healthy donors. Then, we used a humanized mouse model to validate the therapeutic efficacy of expanded γδ T cells in vivo; furthermore, the expanded γδ T cells were adoptively transferred into late-stage liver and lung cancer patients. We found that the expanded cells possessed significantly improved immune effector functions, including proliferation, differentiation, and cancer cell killing, both in vitro and in the humanized mouse model. Furthermore, a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells. Among these 132 patients, 8 liver cancer patients and 10 lung cancer patients who received ≥5 cell infusions showed greatly prolonged survival, which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy. Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy, which will inspire further clinical investigations and eventually benefit cancer patients.