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.
Highlights
The programmed cell death protein 1 receptor (PD-1) receptor was first described in the early 1990s given its expression during induction of apoptosis in a T-cell hybridoma [1, 2]
Preclinical evidence suggested that activation of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling could serve as a mechanism for tumors to evade an antigen-specific T-cell immunologic response [6,7,8]
Median Overall survival (OS) was significantly improved with pembrolizumab compared to chemotherapy (HR 0.57, 95% Confidence interval (CI) 0.37-0.88, p = 0.005) in those with PD-L1 expression ≥10% but there was no difference in Progression-free survival (PFS) between arms in this population
Summary
The programmed cell death protein 1 receptor (PD-1) receptor was first described in the early 1990s given its expression during induction of apoptosis in a T-cell hybridoma [1, 2]. Since its initial discovery several groups have identified that engagement of PD-1 through its ligand, programmed death ligand 1 (PD-L1), negatively regulates T-cell-mediated immune responses [3,4,5,6]. The Initial phase I studies investigating several humanized monoclonal IgG4 antibodies targeting PD-1 and PD-L1 in advanced solid tumors were soon conducted and paved way for the development of the first PD-1 inhibitors, nivolumab and pembrolizumab, approved by the Food and Drug Administration (FDA) [9,10,11]. Immune checkpoint inhibitors targeting the PD-1/PDL1 axis are approved in the treatment of several malignancies ranging from classical Hodgkin lymphoma to head and neck squamous cell carcinoma (HNSCC) [12].
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