title: Clinical development of mAbs to block the PD1 pathway as an immunotherapy for cancer.
abstract: Tumor antigen-specific T-cell function is regulated by both positive and negative costimulatory signals, which are received in the secondary lymphoid organs and within the tumor microenvironment. Tumor-induced T-cell dysfunction results from a lack of positive costimulatory signals, combined with a predominance of negative immunoregulatory mechanisms. The engagement of the protein programmed death 1 (PD1), expressed on activated T-cells, by programmed death ligand 1 (PD-L1)/B7H1 within tumor cells or other host-derived cells results in the downregulation of T-cell function, and represents an important negative regulatory pathway. Preclinical cancer models suggest that interruption of PD1/PD-L1 interactions leads to improved antitumor T-cell responses and tumor control. mAbs developed against both PD1 and PD-L1/B7H1 are being evaluated in phase I/II clinical trials in patients with a variety of cancers. The uncoupling of negative immune regulatory pathways therefore represents an exciting and potentially highly valuable new modality for cancer immunotherapy.
authors.affiliation: University of Chicago, Department of Medicine and Pathology, Section of Hematology/Oncology, 5841 South Maryland Avenue, Chicago, IL 60637, USA. jkline@medicine.bsd.uchicago.edu
authors.forename: Justin
authors.initials: J
authors.lastname: Kline
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab