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

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.

Vγ9Vδ2 T cells strengthen cisplatin inhibition activity against breast cancer MDA-MB-231 cells by disrupting mitochondrial function and cell ultrastructure

“…Cis-platinum has been used as clinical therapy drug against breast cancer for many years, however, its severe side effects limited the treatment efficacy clinically. V9V2 T cell has been increasingly recognized as new therapy strategy for cancer, since this cell could regulate immune function of the patients [15,16,19]. Immunotherapy including immune cells-based approach has become a new frontier of tumor therapy, but chemotherapy drug-based traditional protocol still plays an important role clinically.…”

“…V9V2 T cell belongs to one subset of human peripheral  T cell, one major component of T lymphocytes (the other is αβ T cell). V9V2 T cells showed promising clinical value because of the potent anti-tumor activity [15][16][17], thus could be developed into a new strategy [13,15,16,[18][19][20] for breast cancer immunotherapy. For example, V9V2 T cells could inhibit breast cancer cell proliferation by regulating crucial molecules related to cell survival and apoptosis [21]; V9V2 T cells exerted promising breast tumor inhibition activity in the context of zoledronic acid pre-treatment [22]; notably, clinical Phase I trial study on breast cancer patients revealed that sustained population of V9V2 T cells were positively correlated with sound prognosis [23].…”

Vγ9Vδ2 T cells strengthen cisplatin inhibition activity against breast cancer MDA-MB-231 cells by disrupting mitochondrial function and cell ultrastructure

“…Cis-platinum has been used as clinical therapy drug against breast cancer for many years, however, its severe side effects limited the treatment efficacy clinically. Vγ9Vδ2 T cell has been increasingly recognized as new therapy strategy for cancer, since this cell could regulate immune function of the patients [ 16 , 17 , 20 ]. Immunotherapy including immune cells-based approach has become a new frontier of tumor therapy, but chemotherapy drug-based traditional protocol still plays an important role clinically.…”

“…The methodology of γδ T cell isolation and culture had been described in detail in previous reports [ 16 , 17 , 26 , 27 ]. Briefly, the peripheral blood was collected from healthy donors, then peripheral blood monocyte cells (PBMCs) were isolated using the Ficoll-Paque centrifugation protocol, following by culturing PBMCs in RPMI-1640 culture medium supplemented with 10% fetal bovine serum (FBS), IL-2 (5 ng/ml) and zoledronate (10 nM).…”

“…Vγ9Vδ2 T cell belongs to one subset of human peripheral γδ T cell, one major component of T lymphocytes (the other is αβ T cell). Vγ9Vδ2 T cells showed promising clinical value because of the potent anti-tumor activity [ 16 – 18 ], thus could be developed into a new strategy [ 13 , 16 , 17 , 19 – 21 ] for breast cancer immunotherapy. For example, Vγ9Vδ2 T cells could inhibit breast cancer cell proliferation by regulating crucial molecules related to cell survival and apoptosis [ 22 ]; Vγ9Vδ2 T cells exerted promising breast tumor inhibition activity in the context of zoledronic acid pre-treatment [ 23 ]; notably, clinical Phase I trial study on breast cancer patients revealed that sustained population of Vγ9Vδ2 T cells were positively correlated with sound prognosis [ 24 ].…”