PT  - JOURNAL ARTICLE
AU  - Jun Gong
AU  - Alexander Chehrazi-Raffle
AU  - Srikanth Reddi
AU  - Ravi Salgia
TI  - Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations
AID  - 10.1186/s40425-018-0316-z
DP  - 2018 Dec 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - 8
VI  - 6
IP  - 1
4099  - http://jitc.bmj.com/content/6/1/8.short
4100  - http://jitc.bmj.com/content/6/1/8.full
SO  - J Immunother Cancer2018 Dec 01; 6
AB  - Early preclinical evidence provided the rationale for programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) blockade as a potential form of cancer immunotherapy given that activation of the PD-1/PD-L1 axis putatively served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity. Early-phase studies investigating several humanized monoclonal IgG4 antibodies targeting PD-1 and PD-L1 in advanced solid tumors paved way for the development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved by the Food and Drug Administration (FDA) in 2014. The number of FDA-approved agents of this class is rapidly enlarging with indications for treatment spanning across a spectrum of malignancies. The purpose of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy to date. In particular, we focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies in cancer. As the number of PD-1/PD-L1 inhibitors continues to grow, predictive biomarkers, mechanisms of resistance, hyperprogressors, treatment duration and treatment beyond progression, immune-related toxicities, and clinical trial design are key concepts in need of further consideration to optimize the anticancer potential of this class of immunotherapy.Abbreviations:AEsAdverse eventsALTAlanine aminotransferaseASCTAutologous stem cell transplantationASTAspartate aminotransferaseAUCArea under the curveBVBrentuximab vedotincHLClassical Hodgkin lymphomaCIConfidence intervalCPKCreatine phosphokinaseCRCColorectal carcinomaCTLA-4Cytotoxic T-lymphocyte antigen 4dMMRMismatch repair deficientFDAFood and drug administrationHCCHepatocellular carcinomaHNSCCHead and neck squamous cell carcinomaHRHazard ratioICCInvestigator-choice chemotherapyIDOIndoleamine 2,3-dioxygenaseIFNInterferonIHCImmunohistochemistryIRF1Interferon regulatory factor 1IVIntravenousLAG3Lymphocyte activation gene 3 proteinMSI-HMicrosatellite instability-highMSSMicrosatellite stableNSCLCNon-small cell lung cancerORROverall response rateOSOverall survivalPD-1Programmed cell death 1PD-L1Programmed death-ligand 1PFSProgression-free survivalRCCRenal cell carcinomaTBPTreatment beyond first progressionTCRT-cell receptorTIGITT-cell immunoglobulin and ITIM domain (TIGIT)TILsTumor-infiltrating lymphocytesTKITyrosine kinase inhibitorTMETumor microenvironmentTPSTumor proportion scoreTTFTime-to-treatment failureUCUrothelial carcinomaVEGFVascular endothelial growth factor