4.2.1 Mechanism of Action of PD-1 and PD-L1 Inhibi...
The PD-1 receptor was first described in the early 1990s, given its expression during induction of apoptosis in a T-cell hybridoma.Since its initial discovery several groups have identified that engagement of PD-1 through its ligand (PD-L1), negatively regulates T-cell-mediated immune responses.Early preclinical evidence suggested that activation of PD-1/PD-L1 signaling could serve as a mechanism for tumors to evade an antigen-specific T-cell immunologic response.Consequently, the hypothesis was developed that PD-1/PD-L1 blockade might be an effective cancer immunotherapy (Figure 4.2) [9].
Figure 4.2 Mechanism of action of PD-1 and PD-L1 inhibitors.The programmed cell death 1 (PD-1)receptor is expressed on activated T cells, B cells, macrophages, regulatory T cells (Tregs), and natural killer (NK) cells.Binding of PD-1 to its B7 family of ligands, programmed death ligand 1 (PD-L1 or B7-H1) or PD-L2 (B7-DC) results in suppression of proliferation and immune response of T cells.Activation of PD-1/PD-L1 signaling serves as a principal mechanism by which tumors evade antigen-specific T-cell immunologic responses.Antibody blockade of PD-1 or PD-L1 reverses this process and enhances antitumor immune activity.(Please scan the QR code on the Preface to get original color figures.)
Source: Gong J, Chehrazi-Raffle A, Reddi S, Salgia R.“Development of PD-1 and PD-L1 Inhibitors as a Form of Cancer Immunotherapy: A Comprehensive Review of Registration Trials and Future Considerations”.JournalofImmunoTherapyofCancer, 2018, 6(1):8.
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 US FDA.Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis are now approved in the treatment of several malignancies ranging from classical Hodgkin lymphoma to head and neck squamous cell carcinoma (HNSCC).Since the approval of pembrolizumab for the treatment of advanced melanoma in September 2014, the clinical development of PD-1 and PD-L1 inhibitors as anticancer agents has broadened, as described in Table 4.1.In 2018, the US FDA has approved PD-1/PD-L1 inhibitors for the treatment of nine cancer types (Figure 4.3) [9].(https://www.daowen.com)
Table 4.1 Overview of PD-1/PD-L1 inhibitors,mechanisms of action,trial designations and approved companion diagnostics [9]
Figure 4.3 T imeline of US FDA approvals for PD-1 and PD-L1 inhibitors in can cer therapy.The US FDA approvals of programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1)inhibitors detailed by agent, date of approval, and tumor type.(Please scan the QR code on the Preface to get original color figures.)
Source: Gong J, Chehrazi-Raffle A, Reddi S, Salgia R.“Development of PD-1 and PD-L1 Inhibitors as a Form of Cancer Immunotherapy: A Comprehensive Review of Registration Trials and Future Considerations”.JournalofImmunoTherapyofCancer, 2018, 6(1):8.