Cancer immunotherapy harnessing γδ T cells and programmed death-1.

Abstract

Cancer immunotherapy has received increasing attention since the success of CTLA-4 and programmed death-1 (PD-1) immune checkpoint inhibitors and CAR-T cells. One of the most promising next-generation cancer treatments is adoptive transfer of immune effector cells. Developing an efficacious adoptive transfer therapy requires growing large numbers of highly purified immune effector cells in a short period of time. γδ T cells can be effectively expanded using synthetic antigens such as pyrophosphomonoesters and nitrogen-containing bisphosphonates (N-BPs). Pyrophosphomonoester antigens, initially identified in mycobacterial extracts, were used for this purpose in the early years of the development of γδ T cell-based therapy. GMP-grade N-BPs, which are now commercially available, are used in many clinical trials worldwide. In order to develop N-BPs for cancer immunotherapy, N-BP prodrugs have been synthesized; among these, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA) is the most potent compound for stimulating γδ T cells. The activated γδ T cells express high levels of PD-1, suggesting the potential for a combination therapy harnessing γδ T cells and PD-1 immune checkpoint inhibitors. In addition, the functions of γδ T cells can be modified by IL-18. Collectively, the recent findings show that γδ T cells are one of the most promising immune effector subsets for the development of novel cancer immunotherapy.