Which Patients Will Benefit from Immunotherapy for Cancer? Some Hints Emerge

December 17, 2014, by NCI Staff

A relatively small but growing number of patients with cancer have benefited from treatments that use the body’s immune system to fight tumors. Some patients have had dramatic responses to these treatments—called immunotherapies—but little is known about which patients and which types of cancer are likely to respond. A flurry of new studies could provide some clues.

In one study, researchers identified a “genetic signature” in the tumors of patients with advanced melanoma who responded to a form of immunotherapy called checkpoint blockade. The results could be the basis for a test that identifies likely responders to this treatment as well as for developing new treatments, the researchers said in a news release.

The study, which appeared in the New England Journal of Medicine, identified specific molecules, called neo-antigens, in the tumors of patients who responded to checkpoint blockade therapy but not in the tumors of patients who did not respond to such therapy. Neo-antigens arise when gene mutations cause protein changes that make the altered proteins appear “foreign” to the immune system, thereby triggering an immune response.

By examining the mutations in the tumor DNA of 25 patients who had been treated with ipilimumab (Yervoy) or a related drug, tremelimumab, the researchers were able to identify a number of mutations and corresponding neoantigens that were shared among the patients who had long-term clinical benefit from checkpoint blockade therapy, but were completely absent in patients who had minimal or no benefit. The researchers then validated their findings using the tumor DNA from 39 additional patients.

Both ipilimumab and tremelimumab block the activity of a “checkpoint” protein called CTLA4. Checkpoint proteins normally keep immune responses in check to prevent overly strong responses that might damage normal cells as well as abnormal cells. Blocking CTLA4 is designed to lift the brakes on the immune system, enabling it to destroy cancer cells. In the current study, some of the mutations changed certain proteins in such a way that segments of the proteins resembled protein segments from infectious bacteria and viruses, the researchers found.

Identifying those likely to respond is an important next step in the development of these agents, commented James Gulley, M.D., Ph.D., of NCI’s Center for Cancer Research.

“It would be a great advance to have a test that could help to identify patients more likely to respond to anti-CTLA4 antibodies alone and which patients may benefit from other, perhaps experimental, approaches such as the combination of immunotherapy agents,” Dr. Gulley said.

The study authors, including Timothy Chan, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center (MSKCC), plan to repeat their analysis on other immunotherapies and other types of cancer, such as lung cancer.

Five additional immunotherapy studies were recently published online in Nature with an accompanying commentary by Drs. Chan and Jedd Wolchok, M.D., Ph.D., also from MSKCC.

Collectively, they wrote, the five studies “reveal a growing list of cancers that respond to checkpoint blockade and describe characteristics of those patients who respond to such therapies.”