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J Immunother Cancer. 2018 Jan 23;6(1):8. doi: 10.1186/s40425-018-0316-z.

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

Author information

1
Department of Medical Oncology, City of Hope National Medical Center, 1500 E Duarte St, Duarte, CA, 91010, USA.
2
Department of Internal Medicine, Harbor-UCLA Medical Center, 1000 W Carson St, Torrance, CA, 90509, USA.
3
Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Building 51, Room 101, 1500 E Duarte St, Duarte, CA, 91010, USA. rsalgia@coh.org.

Abstract

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.

KEYWORDS:

Biomarkers; Clinical trials; Hyperprogressors; Immune checkpoint; Immune-related toxicity; Microbiome; PD-1 inhibitor; PD-L1 inhibitor; Treatment beyond progression

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