Unleashing the immune system against cancer

A multicenter team that included Yale scientists has reported one of the first significant successes in harnessing the immune system to fight cancer. In an early clinical trial of a new cancer drug, the scientists said in a report published on June 2 in the New England Journal of Medicine, tumors regressed significantly in between 20 and 33 percent of patients with non-small-cell lung cancer, kidney cancer, or melanoma.

The response in lung cancer patients was remarkable, said Mario Sznol, M.D., professor of medicine, because immunotherapies had generally been effective only in melanoma and kidney cancers. (For reasons that are not fully understood, the small number of patients with colorectal or prostate cancer in the trial—which had 296 patients—did not respond to the drug.) The patients in this trial had already received heavy doses of therapies that likely depleted their immune systems. If administered to patients with less prior treatment, the drug should be even more effective, said Lieping Chen, M.D., Ph.D., professor of immunobiology, of dermatology, and of medicine. The study, said Sznol, also found consistent, durable regression of cancers: 20 of 31 responses that were tracked lasted for at least a year—a result rarely observed with traditional chemotherapy or forms of therapy that target specific characteristics of tumors. The drug, BMS-936558, which was developed by Bristol-Myers Squibb, acts by blocking a protein that tumors use to disable the body’s immune system, and represents a new approach to cancer therapy. “We’re just at the beginning of a paradigm shift in the treatment of cancer,” said Sznol.

Since similar results were seen at all nine centers participating in the trial, Sznol considers it highly unlikely that the drug’s effectiveness is a fluke. Scott N. Gettinger, M.D., associate professor of medicine, who recruited lung cancer patients for the trial, said that the response in those patients “opens the door to looking at other solid tumors.” Most of his patients had few or none of the side effects often associated with chemotherapy—hair loss, drops in blood-cell counts, altered taste, and profound fatigue. “This is the best-tolerated drug I have ever given to patients with lung cancer,” Gettinger said.

The new drug has its roots in the labors of Chen, who was training to be an oncologist in the 1980s. The lack of effective cancer treatments made it a depressing job. “That’s why I quit clinical practice,” Chen said. He shifted to research, focusing on the role of the immune system in cancer.

For decades scientists have sought to understand why the human immune system sits on the sidelines when cancer invades the body, and how to provoke it to attack cancer cells. Such an approach could target the disease while sparing normal cells, resulting in greater effectiveness and fewer side effects. And because the immune system “remembers” invaders it has encountered, the response to immunotherapy should be long-lasting.

A decade’s research by Chen and colleagues at other institutions found that the interactions of certain proteins and receptors allow tumor cells to disable T cells, the immune system’s main fighters. The tumor cells, Chen said, take advantage of a mechanism that the body uses to prevent damage from prolonged immune responses. In 1991 Chen, then at the Mayo Clinic, discovered B7-H1, a protein that can suppress T cells. Nine years later researchers from Harvard Medical School’s Dana-Farber Cancer Institute and the University of Kyoto found that B7-H1 binds to programmed death 1 (PD-1), a receptor on the surface of T cells. Scientists renamed the B7-H1 protein, calling it PD-L1 to reflect its role as a binding partner for PD-1. Tissues use PD-L1 to turn off the immune response when it’s gone on too long; and, Chen found, PD-L1 is overexpressed in many human tumors.

“Cancer steals this mechanism,” said Chen. Cancer triggers an immune response, which sends T cells to attack the tumor. The tumor, in response to signaling molecules from the T cells, expresses PD-L1, which binds to PD-1 and suppresses the T cells. BMS-936558 blocks the PD-1 binding site and keeps PD-L1 at bay.

Tests on tumor samples from the recent trial revealed that tumors that did not express PD-L1 did not respond to treatment, while 36 percent of PD-L1-positive tumors showed a response. That suggests that PD-L1 may serve as a biomarker to identify patients who will benefit from anti-PD-1 drugs. There are side effects of PD-1 blockage—in the current trial, three patients died of drug-related lung inflammation—but Chen thinks that adverse effects can be managed.

Jedd D. Wolchok, M.D., Ph.D., of Memorial Sloan-Kettering Cancer Center, who was not involved in the current trial, said that the new results are encouraging for the potential of immunotherapy in the treatment of cancer. Following the success of the drug ipilimumab, which also blocks a molecule expressed on the surface of T cells, the findings are the second clear demonstration that unleashing the immune system can produce durable regressions in cancer.

Although BMS-936558 was effective when used alone, the Yale researchers believe that it will be most useful when combined with other therapies.

“I have patients who have benefited enormously from this drug,” Sznol said. And while current treatments prolong life for months or a couple of years, Sznol said, “these new therapies may eventually offer the possibility of cure.”