An immune checkpoint inhibitor is a drug that unleashes an immune system attack on cancer cells. Often made of antibodies, checkpoint inhibitors act on the immune system, therefore such drugs are known as immunotherapies.
How do checkpoint inhibitors work?
Checkpoint inhibitors seek to overcome one of cancer’s main defenses against an immune system attack.
Immune system T cells patrol the body constantly for signs of disease or infection. When they encounter another cell, they probe certain proteins on its surface, which serve as insignia of the cell’s identity. If the proteins indicate the cell is normal and healthy, the T cell leaves it alone. If the proteins suggest the cell is infected or cancerous, the T cell will lead an attack against it. Once T cells initiate an attack, the immune system increases a series of additional molecules to prevent the attack from damaging normal tissues in the body. These molecules are known as immune checkpoints.
Tumor cells often wear proteins that reveal the cells’ cancerous nature, but they sometimes commit what might amount to identity theft, arraying themselves in proteins of normal cells. Research has shown that cancer cells often utilize immune checkpoint proteins such as CTLA-4 and PD-L1 to suppress and evade an immune system attack. Deceived by these normal-looking proteins, T cells may allow the tumor cell to go undisturbed.
Checkpoint inhibitors come into play here, blocking these normal proteins on cancer cells, or the proteins on T cells that respond to them. The goal is to remove the blinders that prevented the T cells from recognizing the cells as cancerous and ultimately for the immune system to lead an assault on them.
Which cancers can checkpoint inhibitors work for?
Seven checkpoint inhibitors have been approved by the FDA for cancer. They include ipilimumab, which blocks CTLA-4; atezolizumab, avelumab, and durvalumab, which block PD-L1; and nivolumab, pembrolizumab, and cemiplimab, which block the PD-1 protein on T cells that links up with PD-L1.
Each drug is approved for specific types and stages of cancer, either as a standalone treatment or in combination with other drugs. The types of cancer include:
What’s more, these medicines are showing promise in clinical trials involving other types of cancer. In many cases, checkpoint inhibitors are paired with other drugs — such as chemotherapy agents — in cancer treatment.
“It makes sense to test these agents in every form of cancer,” says Dana-Farber’s Gordon Freeman, PhD, whose lab discovered that PD-L1 resides on normal cells as well as some cancer cells, and that blocking it can provoke an immune system attack on tumors.
Learn more about the science of immunotherapy and checkpoint inhibitors in the video below:
About the Medical Reviewer
Gordon Freeman, PhD, Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School, is renowned for discovering the PD-L1 and PD-L2 proteins. Dr. Freeman showed that PD-L1 and PD-L2 bound to PD-1 to turn off the immune response and that blockade of PD-L1/PD-1 enhanced immune responses. He further showed that PD-L1 is highly expressed on many tumors and allows these tumors to resist immune attack. Dr. Freeman’s work led directly to the development of a successful strategy for cancer immunotherapy - blocking the PD-1-ligand interaction. Dr. Freeman has published over 400 scientific papers and holds over 90 US patents on immunotherapies. He was elected to the National Academy of Sciences and the National Academy of Inventors, is a Fellow of the AACR and SITC Academies, and has received numerous awards, including the William B. Coley Award for Distinguished Research in Tumor Immunology, the Warren Alpert Foundation Prize, and the Richard Smalley, MD, Memorial Award. Dr. Freeman received his Ph.D. degree in Microbiology and Molecular Genetics from Harvard University.