In the 1980s, immunotherapy researcher Lieping Chen, M.D., Ph.D., embraced the career goal of curing one cancer. That lofty-seeming goal is beginning to look more modest today. Recent clinical trials have shown that one cancer after another is vulnerable to immune modulation therapy, a cancer-fighting strategy Chen pioneered that for years was considered marginal.
“Now it seems like I should retire, because I think these drugs can probably cure multiple cancers,” says Chen, the United Technologies Corporation Professor in Cancer
Research at the School of Medicine. “This is way beyond my expectations already. I’m very happy.”
The drugs Chen refers to are a group of immune modulation agents called PD-1/PD-L1 inhibitors. These are antibodies that allow the immune system to attack tumors by blocking a pathway that paralyzes the immune response, and they’ve achieved dramatic clinical trial results for melanoma.
In September the FDA approved pembrolizumab (marketed as Keytruda) for advanced melanoma, while Japan approved nivolumab for the cancer in July. These drugs have also shown startling effects in kidney and lung cancer—the latter result a game-changer, since lung cancer is responsible for more deaths than any other cancer.
These advances appear to be just the start. Alone and in combination with many other agents, PD-1/PD-L1 inhibitors are currently under intense scrutiny in hundreds of studies around the world, showing promise for treating Hodgkin’s lymphoma, bladder, stomach, ovarian, and head and neck cancers. At Yale, researchers are building on groundbreaking results from the last several years to study these agents in a wide variety of solid and hematologic tumors.
In July, Mario Sznol, M.D., professor of medicine, updated colleagues at the annual conference of the American Society of Clinical Oncology (ASCO) on a remarkable Phase I melanoma trial. It combines nivolumab and another antibody, ipilimumab, in advanced melanoma patients. While ipilimumab acts on the unrelated CTLA-4 checkpoint, together the drugs affect the immune system synergistically. Nivolumab produces an already impressive 63 to 73 percent one-year survival rate, but when combined with ipilimumab the rates rose to 85 percent at one year and 79 percent at two years. (By comparison, chemotherapy offers this population of patients a two-year survival rate of around 20 percent.) Early results appeared in 2013 in the New England Journal of Medicine. If confirmed in Phase III trials, Sznol says, “this would be the most active combination that we’ve ever developed for melanoma.”
Another PD-1/PD-L1 inhibitor, MPDL3280A, is in trial as well. Half of a group of patients with advanced bladder cancer—who haven’t responded to standard therapy—have responded to MPDL3280A, says investigator Daniel P. Petrylak, M.D., professor of medicine and urology. That, he says, “has been pretty much unheard of,” since no chemotherapeutic agent currently exceeds a 20 percent response rate. Some patients’ tumors have become radiologically undetectable, and responses have lasted more than 18 months. Similarly, in 2013, Roy S. Herbst, M.D., Ph.D., Ensign Professor of Medicine, professor of pharmacology, and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, reported at ASCO that MPDL3280A was durably shrinking advanced solid and hematologic tumors in 21 percent of patients.
Such results are prompting oncologists to rethink the role of chemotherapy, which damages the immune system as it targets fast-dividing cancer cells. Immunotherapy, by contrast, relies on intact immunity. That difference makes it problematic to design trials that combine immunotherapeutic and chemotherapeutic agents. But it also means researchers like Chen foresee a day when immunotherapy will replace chemo as a first-line treatment for cancer. “The direction is very clear,” says Chen, also professor of immunobiology, dermatology, and medicine.
Studies that place the burden of a cure solely on immunotherapeutic agents are already under way. Scott N. Gettinger, M.D., associate professor of medicine, for example, is studying nivolumab alone or in combination with other agents in advanced lung cancer, with promising early results.
PD-1/PD-L1 inhibitors work by disrupting an immune “shutdown” caused by tumors. Typically, when the immune system’s T-cells arrive at cancer sites, they secrete cytokines, which causes tumors and related tissues to make the protein PD-L1. The PD-L1 then binds to PD-1, a receptor on the arriving T-cells, paralyzing the immune response at the tumor site. PD-1/PD-L1 inhibitors come in two types: drugs that consist of antibodies to PD-1, such as nivolumab, and drugs that consist of antibodies to PD-L1, such as MPDL3280A. Both types counteract this immune shutdown, allowing T-cells to proceed with the destruction of cancer cells. (Incidentally, Chen discovered PD-L1 in 1999 at the Mayo Clinic.)
The PD-1/PD-L1 inhibitors offer multiple and distinct advantages. Not only do they halt and shrink so many advanced cancers, their effects also last much longer than those of chemotherapy, since the inhibitors bolster the patient’s immune system against his own cancer. And because the immune boost happens at tumor sites, most side effects are minor or readily manageable, so the drugs are better tolerated than chemotherapy. “Patients don’t even have to be hospitalized,” Chen says. “They walk in, sit for a half-hour or one hour, and then leave.”
Yale researchers hope to develop biomarkers to identify the patients most likely to benefit from immunotherapeutic agents from those less likely, so they’re taking biopsies from responders and non-responders to look for key differences (see related story, “Better predicting a tumor’s treatability”). Some tumors, for example, express more PD-L1 than others, and so are more apt to respond to an anti-PD-1/PD-L1 agent.
Researchers also plan to develop effective combinations with other immune modulatory agents as yet undeveloped and with other immunotherapy strategies. From here, the possibilities seem nearly limitless.
“We used to have a paradigm in oncology that the amount of excitement is inversely correlated to the amount of clinical data that you have,” Sznol says. “Here, the excitement is actually driven by very good clinical data. We’re just at the beginning of what we can do with these drugs.”