Xu et al. developed a new formula (NF) for in vitro Vγ9Vδ2 T cell expansion by adding IL-15 and Vitamin C to the commonly used IL-2 and Zolendrate. NF-expanded Vγ9Vδ2 T cells showed increases in proliferation, costimulatory molecule expression, cellular energy metabolism, cytotoxicity; enrichment of terminally differentiated effector memory cells; and decreases in Vγ9Vδ2 T cell apoptosis. NF-expanded Vγ9Vδ2 T cells infused into humanized tumor-bearing mice demonstrated increased tumor control and prolonged mouse survival. In late-stage liver and lung cancer patients, NF-expanded allogeneic Vγ9Vδ2 T cells had no significant adverse effects and increased OS.
Contributed by Shishir Pant
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.