PD-L1 inhibitor

Atezolizumab for Bladder Cancer - National Cancer Institute

src: www.cancer.gov

PD-L1 inhibitors are a group of novel drugs that 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 and occurs following infection to limit the killing of bystander host cells and prevent autoimmune disease. This immune checkpoint is also active in pregnancy, following tissue allografts and in different types of cancer.

Video PD-L1 inhibitor

Cancer immunotherapy

In the cancer disease state the interaction of PD-L1 on the tumour cell surface with PD-1 on a T-cell reduces T-cell function signals to prevent the immune system from attacking the tumour cells. Use of a PD-L1 inhibitor that blocks the interaction of PD-L1 with the PD-1 receptor can prevent the cancer from evading the immune system responses in this way. Several PD-L1 inhibitor antibodies are being successfully trialled within the clinic for use in advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma, amongst other cancer types.

Immunotherapy with these immune checkpoint inhibitors appears to shrink tumours in a higher number of patients across a wider range of tumour types and is associated with lower toxicity levels than other immunotherapies, with durable responses. However, de-novo and acquired resistance is still seen in a large proportion of patients. Hence PD-L1 inhibitors are considered to be the most promising drug category for many different cancers.

Maps PD-L1 inhibitor

Therapeutics

Few PD-L1 inhibitors have been approved for use to date, though extensive target validation has been shown through phase II and III clinical trials using different monoclonal antibody therapies.

The PD-L1 inhibitor atezolizumab (MPDL3280) is a fully humanised, engineered, IgG1 antibody developed by Roche Genentech. It has shown promising results in Phase I trials in the treatment of a number of different cancers, including melanoma, lung, bladder and renal cancer. Atezolizumab in the treatment of urothelial bladder cancer has completed phase II trials. Phase II and III trials of this compound in the treatment of non-small cell lung cancer are now underway and a decision from the FDA is expected later in 2016 regarding the drug's approval.

In May 2016 FDA granted accelerated approval to atezolizumab for locally advanced or metastatic urothelial carcinoma treatment after failure of chemo or radio therapy.

Avelumab (MSB0010718C) is a fully human IgG1 antibody developed by Merck KGaA and Pfizer. It has completed Phase I trials for metastatic or locally advanced solid tumours. Avelumab has been FDA approved for the treatment of Merkel-cell carcinoma and Phase III trials have been reached for this drug in the treatment of non-small cell lung cancer.

Durvalumab is an anti-PD-L1 antibody developed by AstraZeneca. Phase III trials for the treatment of metastatic urothelial bladder cancer in combination with an alternative immune checkpoint inhibitor have been reached.