Why does immunotherapy work for some but not others?

Researchers and doctors are trying to unravel the mystery behind why in some cases, about half the time immunotherapy is tried on most cancers, the patient's immune system doesn't respond at all.

When an immunotherapy drug comes knocking on cancer's door and there is no response, doctors and researchers may not always know why. Did the patient's immune system simply not answer? Or did the cancer turn off the lights and act like no one is home? "Not everyone responds to these drugs right now," says Dr. Pamela Crilley, Chair of the Department of Medical Oncology for Cancer Treatment Centers of America® (CTCA) and Medical Oncologist at CTCA® Philadelphia. "There's ongoing investigation into understanding why that is, and what can be done to increase the response rate.”

Immunotherapy drugs known as checkpoint inhibitors continue to generate buzz, for good reason. Since 2010, when the first such drug, ipilimumab (Yervoy®), was approved to treat advanced melanoma, a number of patients have seen positive results—some with few significant side effects. These drugs work by unmasking cancer cells and exposing them to the immune system for attack. Now researchers and cancer doctors are trying to unravel the mystery behind why in some cases—about half the time immunotherapy is tried on most cancers—the patient's immune system doesn't respond at all.

T-cell exhaustion

Some patients who have little or no reaction to immunotherapy drugs may be suffering from T cell exhaustion, "the scenario where there are not enough available or functioning T cells to mount a response," says Dr. Glen Weiss, Director of Clinical Research at our Phoenix hospital. "They may already be occupied or are not in the right location, or there is something else that's preventing them from reacting." Researchers are exploring how so-called "co-stimulators" may work in jump-starting the production of T cells so they are hardy and plentiful enough to launch an immune response.

Researchers in London, meanwhile, are exploring the role neoantigens may play in preventing immunotherapy from doing its job. An antigen is a molecule on a cell that attracts immune cells. Neoantigens are new antigens that develop on cancer cells. In some cases, researchers found, cancer cells did not produce enough neoantigens to summon T cells to attack the tumor, even after they were exposed by an immunotherapy drug. "The tumors that we think will respond the best [to immunotherapy drugs] have a certain neoantigen burden, but those neoantigens have to be in almost every tumor cell,” Dr. Charles Swanton, a cancer geneticist at the Francis Crick Institute in London, told STATnews.

Understanding post-response relapse

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

Dr. Weiss says relapses and resistance to checkpoint inhibitors are not unexpected or unique to immunotherapies. "You see it with targeted therapies as well," he says. "You can have a patient’s cancer that responds for a period of time, and then ultimately, the cancer develops some form of resistance." Through clinical trials, researchers are exploring new immunotherapy drugs and drug combinations that they hope may open the door to better responses.