Zoledronate facilitates large-scale ex vivo expansion of functional gamma delta T cells from cancer patients for use in adoptive immunotherapy

Background Human gamma delta T cells can be activated by phospho-antigens and aminobisphosphonates such as zoledronate. Because they can kill tumor cells in a major histocompatibility complex (MHC)-unrestricted manner, adoptive transfer of activated gamma delta T cells may represent a novel cancer immunotherapy. We tested whether gamma delta T cells from advanced cancer patients can be expanded by zoledronate. Methods Peripheral blood mononuclear cells from healthy donors and patients with advanced non-small cell lung cancer, bone metastatic breast or prostate cancer, or lung metastatic colorectal cancer, were stimulated with zoledronate (5 mu M) and interleukin (IL)-2 (1000 IU/mL) for 14 days. The phenotype and function of the expanded gamma delta T-cell populations from healthy donors and cancer patients were compared. Results gamma delta T cells from cancer patients and healthy donors responded to zoledronate equally well in terms of both phenotype and function. gamma delta T cells grew rapidly in vitro and expression of effector molecules, such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, perforin, granzyme B, FasL and TRAIL, increased over time. Cytotoxicity peaked on days 12-14, and proliferation continued up to 14 days, during which time > 1 x 10(9) gamma delta T cells could be obtained from a starting sample of 45-70 mL peripheral blood. Discussion Using the agent zoledronate, already widely used in the clinic, we have established that efficient large-scale ex vivo expansion of gamma delta T cells from cancer patients is possible. These cells exert potent cytotoxicity and may be used for autologous cellular immunotherapy of cancer.