Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

• Published in: Journal for immunotherapy of cancer 2018-01, Vol.6 (1), p.8-18, Article 8
• Main Authors: Gong, Jun, Chehrazi-Raffle, Alexander, Reddi, Srikanth, Salgia, Ravi
• Format: Article
• Language: English
• Subjects: Analysis; Antibodies; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antigens; Apoptosis; B cells; Biomarkers; Cancer; Cancer therapies; Clinical trials; Confidence intervals; Drug approval; Drug dosages; Drug therapy; FDA approval; Humans; Hyperprogressors; Immune checkpoint; Immunoglobulin G; Immunotherapy; Immunotherapy - methods; Ligands; Lung cancer; Lymphocytes; Melanoma; Metastasis; Mutation; Neoplasms - immunology; PD-1 inhibitor; PD-L1 inhibitor; Programmed Cell Death 1 Receptor - metabolism; Registration; Registries; Response rates; Review; T cells; Tumors
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1186/s40425-018-0316-z

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.