Why does immunotherapy work with some and not others?

When an immunotherapy drug knocks on the cancer door and there’s no response, doctors and researchers may not always know the cause. Is the patient’s immune system not responding? Or did the Cancer turn off the lights and act like there was no one at home? “Not everyone responds to these medications right now,” says Dr. Pamela Creely, MD, director of the medical oncology department at Cancer Treatment Centers of America. ^® (CTCA) and an oncologist at CTCA ^® Philadelphia “There is ongoing research to understand why this is and what can be done to increase the response rate.”

Immunotherapy drugs known as checkpoint inhibitors continue to be a sensation, and for good reason. Since 2010, when the first drug of its kind, ipilimumab (Yervoy® ⁾ , was approved to treat advanced melanoma, many patients have seen positive results, some with few significant side effects. These drugs work by detecting cancer cells and exposing them to the immune system to attack them. Now, cancer researchers and clinicians are trying to unravel the mystery of why a patient’s immune system almost doesn’t respond in some cases.

T cell depletion

Some patients who have little or no reaction to immunotherapy drugs may experience T-cell depletion, “a scenario in which not enough T cells are available or working to elicit a response,” says Dr. Glenn Weiss, clinical director. Find in our Phoenix Hospital. “They may already be busy or they may not be in the right place, or something else is stopping them from responding.” Researchers are exploring how so-called “cost inducers” can increase the production of T cells to make them resistant and abundant enough to initiate an immune response.

Meanwhile, researchers in London are exploring the role new antigens could play in preventing immunotherapy from doing its job. An antigen is a molecule in a cell that attracts immune cells. Neoantigens are new antigens that develop on cancer cells. The researchers found that in some cases, cancer cells did not produce enough new antigens to invoke T cells to attack the tumor, even after exposure to an immunotherapy drug. “The tumors that we think will respond best [to immunotherapy drugs] have a certain amount of new antigens, but these new antigens should be in almost all cancer cells,” said Dr Charles Swanton, a cancer geneticist at the Francis Crick Institute in London. Statistics News .

Understanding relapse after response

Researchers are also trying to determine why some patients relapse after an initial response to immunotherapy. In separate studies, researchers discovered specific gene mutations in cancers that had developed resistance to immunotherapy drugs. Scientists at MD Anderson, for example, concluded that certain mutations develop resistance to ipilimumab (the CTLA-4 checkpoint inhibitor). The University of California researchers concluded that the JAK1 and JAK2 proteins are resistant to pembrolizumab (a PD-1 checkpoint inhibitor sold as Keytruda). ^® ) in patients who have relapsed after early responses to the drug. In both studies, the researchers concluded that the cancerous mutations disrupted the interferon-gamma signaling pathway, a critical function of the immune system. Interferon gamma (IFN- p) are cancer-fighting cytokines that not only attack cancer cells directly but also act as messenger molecules that help direct the immune response. “This is an additional piece of the puzzle about how to overcome resistance to checkpoint inhibitors,” Dr. James Jolly of the National Cancer Institute (NCI) Cancer Research Center says in a National Cancer Institute blog post about the UCLA study.

Dr. Weiss says relapses and resistance to checkpoint inhibitors are not unexpected or unique to immunotherapies. “You can also see it with targeted therapies,” he says. “You can have a sick cancer that responds over a period of time, and eventually the cancer develops some form of resistance.” Through clinical trials, researchers are exploring new immunotherapy drugs and drug combinations that they hope will open the door to better responses.