Article Text
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.
- PD-1 inhibitor
- PD-L1 inhibitor
- Clinical trials
- Biomarkers
- Immune checkpoint
- Hyperprogressors
- Treatment beyond progression
- Microbiome
- Immune-related toxicity
- AEs
- Adverse events
- ALT
- Alanine aminotransferase
- ASCT
- Autologous stem cell transplantation
- AST
- Aspartate aminotransferase
- AUC
- Area under the curve
- BV
- Brentuximab vedotin
- cHL
- Classical Hodgkin lymphoma
- CI
- Confidence interval
- CPK
- Creatine phosphokinase
- CRC
- Colorectal carcinoma
- CTLA-4
- Cytotoxic T-lymphocyte antigen 4
- dMMR
- Mismatch repair deficient
- FDA
- Food and drug administration
- HCC
- Hepatocellular carcinoma
- HNSCC
- Head and neck squamous cell carcinoma
- HR
- Hazard ratio
- ICC
- Investigator-choice chemotherapy
- IDO
- Indoleamine 2,3-dioxygenase
- IFN
- Interferon
- IHC
- Immunohistochemistry
- IRF1
- Interferon regulatory factor 1
- IV
- Intravenous
- LAG3
- Lymphocyte activation gene 3 protein
- MSI-H
- Microsatellite instability-high
- MSS
- Microsatellite stable
- NSCLC
- Non-small cell lung cancer
- ORR
- Overall response rate
- OS
- Overall survival
- PD-1
- Programmed cell death 1
- PD-L1
- Programmed death-ligand 1
- PFS
- Progression-free survival
- RCC
- Renal cell carcinoma
- TBP
- Treatment beyond first progression
- TCR
- T-cell receptor
- TIGIT
- T-cell immunoglobulin and ITIM domain (TIGIT)
- TILs
- Tumor-infiltrating lymphocytes
- TKI
- Tyrosine kinase inhibitor
- TME
- Tumor microenvironment
- TPS
- Tumor proportion score
- TTF
- Time-to-treatment failure
- UC
- Urothelial carcinoma
- VEGF
- Vascular endothelial growth factor
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.