NKT cell-based immunotherapy for non-small-cell lung cancer

Abstract

 Invariant natural killer T (iNKT) cells are a unique lymphocyte subpopulation that possess an invariant T cell receptor (TCR) and recognize glycolipid antigens, such as α-Galactosylceramide (αGalCer), presenting on CD1d. Activated iNKT cells show a direct and indirect anti-tumor effect by producing effector molecules and cytokines that activate other immune cells, including NK cells and cytotoxic T cells. We are currently focusing on the development of immunotherapy targeting iNKT cells and have conducted early-phase clinical trials for non-small-cell lung cancer (NSCLC). Previous clinical studies have shown that the intravenous injection of αGalCer-pulsed dendritic cells (DCs) induced the activation of endogenous iNKT cells and iNKT cell-dependent responses. Furthermore, an increase in the number of IFN-γ-producing cells among peripheral blood mononuclear cells has been shown to be associated with a prolonged survival. A dramatic infiltration of iNKT cells in the tumor microenvironment was also observed after the injection of αGalCer-pulsed DCs. Based on these results, a phase Ⅱ clinical trials of αGalCer-pulsed DCs for NSCLC were desiged as an Advanced Medical Technology and approved by the Japanese Ministry of Health, Labor and Welfare. Patients with advanced or recurrent NSCLC who had received first-line chemotherapy underwent intravenous injection of α-GalCer-pulsed DCs. αGalCer-pulsed DCs were found to be well-tolerated and prolonged the overall survival. We also discuss future potential combination therapies of iNKT cell-based immunotherapy to achieve enhanced anti-tumor activity and provide better treatment options for patients with advanced NSCLC.