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PD-L1 Immunotherapy

What are PD-1 and PD-L1?

Programmed death-1 (PD-1) ligand 1 (PD-L1), also known as CD274 and B7-H1, is a transmembrane protein commonly expressed on the surface of antigen presenting cells and tumor cells. PD-L1 binds to the PD-1 checkpoint receptor which is commonly found on lymphocytes such as T-cells. The PD-1/ PD-L1 pathway is an immune checkpoint pathway which downregulates T-cell activation and prevents T-cell immunity.

PD-1 also binds PD-L2, commonly known as CD273 and B7-DC. PD-L2 is highly expressed in many epithelial cancers and B-cell lymphomas. PD-L1 is often found on cells from solid tumors and in particular, PD-L1 has been shown to have high expression in ovarian cancer, melanoma and lung cancer. When PD-L2 binds to PD-1, the immune response is downregulated through the upregulation of PD-L1.

In particular, the interaction between PD-1 and PD-L1 leads to the phosphorylation of immune receptor tyrosine–based inhibitory motif (ITIM) and immune receptor tyrosine–based switch motif (ITSM) structure domain's of PD-1. Src homology 2 domain protein tyrosine phosphatase-2 (SHP-2) is then attracted. This leads to the downstream phosphorylation of spleen tyrosine kinase (Syk) and phospholipid inositol-3-kinase (PI3K), which in turn inhibits lymphocyte proliferation and cytokine secretion and much more. This interaction with PD-L1 also plays a role in the development of T regs which contribute to immunosuppression and limit anti-tumor immunity.

The association between the PD-1/PD-L1 pathway and cancer

Tumours often co-opt immune checkpoint protein pathways such as the PD-1/PDL-1 pathway as an immune resistance opportunity. This is why a lot of cancerous cells have high quantities of PD-L1 in order to avoid attack from the immune system. There have been major advancements in cancer therapy through the production of monoclonal antibodies specific for targeting PD-1 and PD-L1.

Atezolizumab is a humanized IgG1 monoclonal anti-PD-L1 antibody that was approved by the U.S Food Drug Administration (FDA) in 2016. Atezolizumab has been approved for the treatment of extensive-stage Small Cell Lung Cancer (SCLC), Metastatic Non-small-cell Lung Cancer (NSCLC), Metastatic Triple-negative Breast Cancer, Unresectable or Metastatic Melanoma, Unresectable or Metastatic Hepatocellular Carcinoma and Locally Advanced or Metastatic Urothelial Carcinoma.

Avelumab, sold under the brand name Bavencio®, was approved by the FDA to be used as a maintenance therapy in people with locally advanced or metastatic urothelial carcinoma who have failed first-line platinum-containing treatment.

Durvalumab is a monoclonal antibody that targets PD-L1. It is used to treat urothelial cancers that are locally advanced or metastatic and have progressed during or following platinum-containing chemotherapy. Durvalumab can also be given to unresectable stage III NSCLC patients who have not had any progress after concurrent platinum-based chemotherapy.

Pembrolizumab, more commonly known as Keytruda®, is a humanized immunoglobulin G1 kappa monoclonal antibody that works by increasing the ability of the immune system to fight against cancer. Specifically, pembrolizumab blocks the interaction between the PD-1 receptor on T-cells and its ligands. Pembrolizumab can be used against many cancers such as breast cancer, colorectal cancer, renal cell carcinoma, skin cancer and much more.

Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to PD-1. This checkpoint inhibitor is used to treat patients suffering from NSCLC, melanoma, renal cell cancer, Hodgkin's lymphoma, urothelial carcinoma, lung cancer and much more.

Cemiplimab is an antibody against PD-1. This checkpoint inhibitor is used to treat metastatic cutaneous squamous cell carcinoma, NSCLC, advanced and metastatic basal cell carcinoma.

21st Jan 2022 Fiona Redmond, PhD

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