PD-1 & PD-L1 Inhibitors

PD-1, also known as programmed cell death 1, is a receptor expressed on the surface of T cells and plays a pivotal role in immune homeostasis, by keeping overstimulated responses at bay while safeguarding tissues from any unintended destruction. In essence, Programmed Cell Death Protein 1 (PD-1) keeps the body's immunity balanced. The ligands for PD-1 are programmed death-ligand 1 (PD-L1) and PD-L2, which are expressed on various cells including cancer cells, antigen-presenting cells, and non-immune cells.

PD-1 and its ligands are powerful players in suppressing immune responses to cancer, chronic infections, and autoimmune diseases. Cancer cells can take advantage of this by upregulating PD-L1; the interaction between PD-L1 and PD-1 on T cells blocks their activation process - granting tumors the opportunity to grow immune system activation.

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.

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.

PD-1 and PD-L1 blocking was first published in 2001 for the treatment of cancer. In 2006, the first clinical trial was launched which evaluated the clinical efficacy of nivolumab. Other PD-1 inhibitors include pembrolizumab and cemiplimab. PD-L1 inhibitors include atezolizumab, durvalumab and avelumab. Studies have shown that PD-1 and PD-L1 inhibitors increase the number of T cells and activate them to fight tumor cells. In addition, these drugs also break down inhibitory pathways on T cells preventing them from being suppressed by the tumor microenvironment. These effects lead to an increased response rate and overall survival in cancer patients.

PD-1 and PD-L1 inhibitors are approved for the treatment of a variety of cancers including non–small cell lung cancer, melanoma, head and neck cancer, renal cell carcinoma and bladder cancer. They have been shown to be effective in both monotherapy or combination therapy with other drugs like chemotherapy or radiation therapy. Clinical trials are underway to evaluate the efficacy of these drugs in other types of cancer.

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.

Dostarlimab was was approved by the FDA in 2021 for the treatment of mismatch repair deficient recurrent or advanced endometrial cancer.