Human γδ T lymphocytes for immunotherapeutic strategies against cancer

Abstract

γδ T lymphocytes are a numerically small subset of T cells with potent cytotoxic activity against a variety of tumor cells. Human γδ T cells expressing the Vγ9Vδ2 T cell antigen receptor recognize endogenous pyrophosphate molecules that are overproduced in transformed cells. Moreover, the intracellular accumulation of such pyrophosphates is strongly enhanced by aminobisphosphonates used in the treatment of osteoporosis and bone metastasis in certain cancer patients. A new concept of cancer immunotherapy is based on the endogenous activation of γδ T cells with aminobisphosphonates plus low-dose interleukin-2.

Figure 1.. Approaches to immunotherapy with γδ T cells

(a) N-BPs inhibit farnesyl diphosphate synthase (FPPS), thus preventing processing of isopentenyl pyrophosphate (IPP) to farnesyl diphosphate (FPP). This leads to accumulation of IPP which then activates Vγ9Vδ2 T cells. Vγ9Vδ2 T cells require exogenous interleukin (IL)-2 for cellular expansion. The combined application of N-BP plus IL-2 leads to in vivo activation of γδ T cells. (b) Alternatively, γδ T cells can be activated in vitro with N-BP or synthetic phosphoantigens in the presence of antigen-presenting cells (APC) and can be subsequently expanded to large cell numbers by an exogenous supply of IL-2 for subsequent adoptive transfer into cancer patients. The cell preparation can be performed under GMP (Good Manufacturing Practice) conditions.