Recent advances in cancer immunotherapy have clearly shown dramatic clinical benefits in some advanced cancer patients. The clinical benefit of immune checkpoint inhibitors, not only in immune responsive tumors, such as melanoma and renal cell carcinoma, but also in non-small cell lung cancer (NSCLC) which was previously considered to be non-responsive, has thus provided proof of the concept for the efficacy of immunotherapy. At the same time, only a limited number of patients successfully responded to immunotherapy and therefore it remains insufficiently effective for many patients. Therefore, combination therapies will likely be required to enhance the anti-tumor activity of immune therapy.

Currently, we focus our attention on the development of invariant natural killer T (iNKT) cell-targeted immunotherapy for NSCLC and head and neck squamous cell carcinoma (HNSCC) to improve the clinical outcome. Previous clinical studies have shown the intravenous injection of a-galactosylceramide (aGalCer)-pulsed antigen presenting cells (APCs) induced the activation of endogenous iNKT cells and iNKT cell-dependent responses. Moreover, an increase in the number of IFN-g producing cells in peripheral blood mononuclear cells has been shown to be associated with a prolonged survival. A dramatic infiltration of iNKT cells and accumulation of conventional T cells in the tumor microenvironment was also observed after aGalCer-pulsed APCs. Based on these results, the phase II clinical trials of aGalCer-pulsed APCs for NSCLC was designed. The protocol treatment in patients with advanced or recurrent NSCLC who received the first line chemotherapy and the follow-up period has now been completed. Data analyses are now planned after the fixation of all data.

The potential of such combination therapies targeting both iNKT cells and other immunotherapies, such as PD-1/PD-L1 inhibitors or tumor antigen specific therapies, has been demonstrated in the preclinical setting. The strategies and future perspectives for iNKT cell-targeting immunotherapy will also be discussed.