Repeated Systemic Administrations of Both Aminobisphosphonates and Human V gamma 9V delta 2 T Cells Efficiently Control Tumor Development In Vivo

Peripheral V gamma 9V delta 2 T lymphocytes compose a major gamma delta T cell subset in primates with broad reactivity against tumor cells. V gamma 9V delta 2 T cells are specifically activated by phosphorylated isoprenoid pathway metabolites called "phosphoagonists." Accordingly, pharmacologic inhibitors of the mevalonate pathway, such as aminobisphosphonates (NBP) that upregulate the intracellular production of phosphoagonists, increase antitumor V gamma 9V delta 2 T cell responses. Immunotherapeutic protocols exploiting GMP-grade agonist molecules targeting human V gamma 9V delta 2 T lymphocytes have yielded promising, yet limited, signs of antitumor efficacy and therefore need to be improved for next-generation immunotherapies. In this study, we used a model of s.c. human tumor xenografts in severely immunodeficient mice to assess the antitumor efficacy of systemic NBP treatments when combined with the adoptive transfer of human V gamma 9V delta 2 T cells. We show that infusion of V gamma 9V delta 2 T cells, 24 h after systemic NBP treatment, efficiently delays tumor growth in mice. Importantly, our results indicate efficient but transient in vivo NBP-induced sensitization of tumor cells to human V gamma 9V delta 2-T cell recognition. Accordingly, repeated and combined administrations of both NBP and gamma delta T cells yielded improved antitumor responses in vivo. Because V gamma 9V delta 2 T cells show similar responsiveness toward both autologous and allogeneic tumors and are devoid of alloreactivity, these results provide preclinical proof of concept for optimized antitumor immunotherapies combining NBP treatment and adoptive transfer of allogeneic human gamma delta T cells.