title: Clinical Development of Immune Checkpoint Inhibitors.
abstract: Recent progress in cancer immunotherapy has been remarkable. Most striking are the clinical development and approval of immunomodulators, also known as immune checkpoint inhibitors. These monoclonal antibodies (mAb) are directed to immune checkpoint molecules, which are expressed on immune cells and mediate signals to attenuate excessive immune reactions. Although mAbs targeting tumor associated antigens, such as anti-CD20 mAb and anti-Her2 mAb, directly recognize tumor cells and induce cell death, immune checkpoint inhibitors restore and augment the antitumor immune activities of cytotoxic T cells by 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 immune checkpoint inhibitors in a variety of cancers. The first in class approved immune checkpoint inhibitor is ipilimumab, an anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) mAb. Two pivotal phase III randomized controlled trials demonstrated a survival benefit in patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved ipilimumab for metastatic melanoma. Several clinical trials have since investigated new agents, alone and in combination, for various cancers. In this review, we discuss the current development status of and future challenges in utilizing immune checkpoint inhibitors.
authors.affiliation: Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan ; Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Tada
authors.affiliation: Department of Experimental Therapeutics, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan ; Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Kitano
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000276:immunology; D004359:Drug Therapy, Combination; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor