PD-1 and PD-L1 inhibitors
The programmed cell death‐1 (PD‐1) protein is widely expressed and found on activated T cells, B cells, and natural killer (NK) cells.
PD-L1 and PD-L2 ligand on tumor cells are assessed with immunohistochemical immunohistochemical testing.
PD ligands are negative regulators of the immune system such that their interactions inhibit effector T cells activation and proliferation by both direct and T regulatory mediated mechanisms.
A combined positive score is the number of PD-L1 staining cells divided by the total number of viable tumor cells, multiplied by 100 and the specimen is considered to express PD-L1 if the CPS is one or higher.
PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anticancer drugs that block the activity of PD-1 and PDL1 immune checkpoint proteins present on the surface of cells.
The PD-L1 immune checkpoint pathway has an essential role in fertility, fetal development, and fetal maternal tolerance.
PD-L1 is found in various tissues including: the placenta, heart, lungs, spleen, lymph nodes, and thymus.
PD-1 is primarily expressed by lymphocytes, whereas PD-L1 and PD-L2 are expressed by antigen presenting cells, including tumor cells.
PD-1 and PD-L1 inhibitors act to inhibit the association of the programmed death-ligand 1 (PD-L1) with its receptor, programmed cell death protein 1 (PD-1).
The interaction of these cell surface proteins is involved in the suppression of the immune system.
The suppression of the immune system to limit the killing of bystander host cells and prevent autoimmune disease.
This immune checkpoint is also active in pregnancy, with tissue allografts, and in different types of cancer.
PD-1/PD-L1 inhibitors:
Nivolumab PD-1
Pembrolizumab PD-1
Atezolizumab PD-L1
Avelumab PD-L1
Durvalumab PD-L1
Cemiplimab PD-1
With cancer, the interaction of PD-L1 on the tumor cells with PD-1 on a T-cell reduces T-cell function signals to prevent the immune system from attacking the tumor cells.
Use of an inhibitor that blocks the interaction of PD-L1 with the PD-1 receptor can prevent the cancer from evading the immune system in this way.
PD-L1 levels have been found to be highly predictive of response.
Higher mutation burden is also predictive of response to anti-PD-1/PD-L1 agents.
PD-1 and PD-L1 inhibitors are closely related to CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitors, such as ipilimumab.
PD-1 and CTLA-4 are both expressed on activated T cells, but at different phases of immune response.
Immunotherapies as a group have toxicities common to them: interstitial pneumonitis, colitis, skin reactions, low levels of platelets and white blood cells, inflammation of the brain or spinal cord, neuromuscular adverse events, including myositis, Guillain-Barr syndrome, myasthenia gravis; myocarditis and cardiac insufficiency, acute adrenal insufficiency, and nephritis.
Compared with standard chemotherapeutic agents, PD-1/PD-L1 inhibitors had a lower reported incidence of fatigue, sensory neuropathy, diarrhea, bone marrow suppression, loss of appetite, nausea, and constipation.