Development of immune checkpoint inhibitors.

Immune checkpoint inhibitors are the most striking innovation in the clinical development of immunotherapy. Monoclonal antibodies (mAbs) restore and augment the antitumor immune activities of cytotoxic T cells by mainly blocking immune checkpoint molecules on T cells or their ligands on antigen-presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies of mAb in various cancers. The A first-in-class approved immune checkpoint inhibitor is ipilimumab, which is a fully humanized mAb that blocks the immunosuppressive signal by cytotoxic T-lymphocyte antigen 4. In 2011, the US Food and Drug Administration approved the use of ipilimumab for the treatment of advanced metastatic melanoma. Then, nivolumab, which is a humanized mAb that blocks programmed death-1 (PD-1), was approved for use in the treatment of advanced melanoma in 2014 and of advanced non-small-cell lung carcinoma (NSCLC) in 2015 in Japan. Pembrolizumab, which is another anti-PD-1 antibody, was approved for use in the treatment of advanced melanoma and advanced NSCLC as the first-line therapy in 2016 in Japan. Thereafter, nivolumab was also approved for use in the treatment of advanced renal cell cancer in August 2016, of Hodgkin's lymphoma in December 2016, and of head and neck cancer in March 2017 in Japan. Moreover, phase III trials of anti-PD-1 mAb and anti-PD-ligand 1 mAb for use in the treatment of cancers, such as gastric, ovarian, bladder, and esophageal cancers, are ongoing. Several clinical trials have investigated new agents, alone and in combination, for use in the treatment of various cancers. Current advances in tumor immunology have unveiled the importance of immunosuppressive cells, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, especially in a tumor microenvironment (TME). Some data from basic research in mouse models and the immunomonitoring of cancer patients suggest that the inhibition of immunosuppressive cells and the cytokines related to them activate and infiltrate cytotoxic T cells and in TME, which could be one of the next combination strategies. The current clinical development of, translational research on, and future challenges in utilizing immune checkpoint inhibitors are described.