An international team of researchers has discovered a new mechanism that will better activate the immune system against cancer. The mechanism allows immune cells to detect and destroy cancer cells better than before, according to the study published this month in the journal Nature. The study was led by Prof Nick Haining, of Harvard Medical School, and co-authored by Prof Erez Levanon, doctoral student Ilana Buchumansky, of the Mina and Everard Goodman Faculty of Life Sciences at Bar-Ilan University, and an international team.
In the study, researchers focused on a mechanism that routinely serves the cell by marking human virus-like genes in order to avoid identifying them as viruses. Together with the Harvard team, Levanon has discovered that “when inhibiting this mechanism, the immune system can be harnessed to fight cancer cells in a particularly efficient manner, and most effectively in lung cancer and melanoma. We found that if the mechanism is blocked, the immune system is much more sensitive,” Levanon said. “When the mechanism is deactivated, the immune system becomes much more aggressive against the tumour cells.”
According to researchers, most patients with cancer either do not respond to immune checkpoint blockade (a type of drug that blocks certain proteins made by some types of immune system cells, such as T cells, and some cancer cells) or develop resistance to it. The National Cancer Institute (NCI) says these proteins help keep immune responses in check and can keep T cells from killing cancer cells. “When these proteins are blocked, the ‘brakes’ on the immune system are released and T cells are able to kill cancer cells better,” says the NCI. Some immune checkpoint inhibitors are used to treat cancer as immunotherapy uses the body’s immune system to fight cancer.
In their study, researchers said they have shown that the loss of function of the RNA-editing enzyme ADAR1 in tumour cells “profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade…this results in growth inhibition and tumour inflammation, respectively.” A new generation of cancer drugs has been developed in recent years which blocks proteins that inhibit immune activity against malignant tumours. “These drugs have shown remarkable success in several tumour types,” say researchers at Bar-Ilan University. In fact, the 2018 Award in Physiology or Medicine, pioneered immunotherapy, which harnesses the body’s immune system to fight cancer. This year’s Nobel Prize in Medicine was awarded to James Allison and Tasuku Honjo, who discovered the key genes of this mechanism. Despite this achievement, the current generation of drugs helps only a small number of patients, while most of the drugs fail to cause the immune system to attack the tumour, researchers said. “It is hoped that the new discovery will allow enhanced activity of the immune system to attack cancer cells. A number of companies have already begun research to screen for drugs that will operate on the basis of this discovery,” the university reported.
A critical function of the immune system is its ability to tell between normal cells in the body and those it perceives as “foreign.” This allows the immune system to attack foreign cells while leaving normal cells alone. To do this, explains the American Cancer Society, the immune system uses “checkpoints” or molecules on certain immune cells that need to be activated (or inactivated) to start an immune response. Still cancer cells can be vicious, often finding ways to use these checkpoints to avoid being attacked by the immune system. The American Cancer Society says the drugs that target these checkpoints do hold a lot of promise as cancer treatments, however.
Drugs known as PD-1 inhibitors such as Pembrolizumab (Keytruda), Nivolumab (Opdivo) and Cemiplimab (Libtayo) have been helpful in treating several types of cancer—including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers and Hodgkin lymphoma. They are also being studied for use against many other types of cancer. “PD-1 is a checkpoint protein on immune cells called T cells. It normally acts as a type of off switch that helps keep the T cells from attacking other cells in the body,” the American Cancer Society explains. “It does this when it attaches to PD-L1, a protein on some normal (and cancer) cells. When PD-1 binds to PD-L1, it basically tells the T cell to leave the other cell alone. Some cancer cells have large amounts of PD-L1, which helps them evade immune attack.” Other drugs known as PD-L1 inhibitors have also been shown to be helpful in treating different types of cancer, including bladder cancer, non-small cell lung cancer and Merkel cell skin cancer (Merkel cell carcinoma), the American Cancer Society reports. They are also being studied for use against other types of cancer. Examples of these drugs include Atezolizumab (Tecentriq), Avelumab (Bavencio) and Durvalumab (Imfinzi).
Many other drugs that target either PD-1 or PD-L1 and other ways of boosting the immune system are now being tested in clinical trials as well, both alone and combined with other drugs. Many different types of vaccines are also currently being studied to treat a variety of cancers, including brain tumours (especially glioblastoma), breast cancer, cervical cancer, colorectal cancer, kidney cancer, lung cancer, lymphoma, melanoma, pancreas cancer and prostate cancer. Click here to read an update from the American Cancer Society on “What’s new in cancer immunotherapy research?”
Credit: Robin Seaton Jefferson for Forbes, 14 January 2019.