New York Times: Drug Helps Defense System Fight Cancer


Published: June 1, 2012

CHICAGO – One of the great frustrations for researchers in the war on cancer is that the body’s own defense system does not do a better job fighting the disease. Tumors, it turns out, have a molecular shield that repels attacks from the immune system.

Now, a new study says, an experimental drug is showing promise in disabling that shield, unleashing the immune system and causing shrinkage of some lung, skin and kidney cancers that had defied treatment with existing drugs.

“We are seeing responses in heavily treated patients – three different cancers, one drug,” Dr. Suzanne L. Topalian, a melanoma specialist at Johns Hopkins University and lead investigator in the study, said in an interview. “This is a group of patients whose life expectancy was measured in a few months.”

The results are from an early clinical trial, and it is not clear whether the drug, developed by Bristol-Myers Squibb, will actually help people live longer. But Dr. Topalian said she was optimistic because when tumors did shrink, they often did not grow back again for more than a year.

The study was discussed Friday at a news conference at the annual meeting of the American Society of Clinical Oncology and is being published online by the New England Journal of Medicine.

The drug, which now goes by the unwieldy code name of BMS-936558, blocks a protein called PD-1. Such PD-1 inhibitors “could be the most exciting clinical and commercial opportunity in oncology,” analysts at Leerink Swann wrote last month. That is partly because such drugs might be able to treat a variety of cancers.

Bristol-Myers said it intended to begin more clinical trials later this year and early next year aimed at winning approval of the drug to treat non-small-cell lung cancer, kidney cancer and melanoma, which is a deadly skin cancer.

Others pursuing drugs that block the action of PD-1 include Merck; the Genentech unit of Roche; GlaxoSmithKline, working with a small Maryland company called Amplimmune; and Teva working with an Israeli biotech company, CureTech.

The early trial, paid for in part by Bristol-Myers, involved 296 patients with various advanced cancers.

Tumors shrank significantly in 18 percent of the lung cancer patients, 28 percent of the melanoma patients and 27 percent of those with kidney cancer. Those rates compare favorably with some existing drugs, according to Leerink Swann.

But the drug did not appear to work for a small number of patients with prostate or colon cancer. And larger studies will be needed to determine whether freeing the immune system leads to side effects, like attacks on parts of the body besides the tumor.

About 14 percent of the patients experienced a severe side effect and three patients died from inflammation of the lung that was apparently tied to the drug.

Still, the results are an improvement to the approach of harnessing the immune system to fight cancer, a field that has had a history of failures.

PD-1, which stands for programmed death 1, is a protein on the surface of activated T cells, the warriors of the immune system. If another molecule, called PD-L1, binds to PD-1, the T cell dies or becomes docile. This is apparently a way that the body regulates the immune system, to avoid an overreaction.

But many cancer cells make PD-L1, which allows them to disarm the T cells just as they are coming to attack the tumor. The Bristol drug is a monoclonal antibody that blocks PD-1 from binding to PD-L1.

Bristol-Myers won approval last year for a drug that removes a different brake on the immune system. That drug, Yervoy, can prolong the lives of people with melanoma, but the unleashed immune system can also lead to severe side effects, like colitis.

PD-1 blockers appear to free up the immune system only around the tumor, rather than more generally.

That could mean that PD-1 will have “fewer side effects and greater anti-tumor activity,” than drugs like Yervoy, Dr. Antoni Ribas, a melanoma specialist at the University of California, Los Angeles, said in an editorial being published in the New England Journal of Medicine.

There is preliminary evidence that PD-1 blockers will not work in people whose tumors do not make PD-L1, as determined by studying a biopsy sample. That might allow the drug to be used only for patients most likely to benefit, researchers said.

PD-1 was discovered in 1992 by Dr. Tasuku Honjo of Kyoto University and colleagues. Some of the work clarifying its role in cancer was done about a decade ago by Dr. Lieping Chen, then at the Mayo Clinic and now a professor of immunobiology and medicine at Yale.

Dr. Chen said that much of cancer immunotherapy has focused on strengthening the immune system or training it to attack the tumor by use of a so-called cancer vaccine. One such vaccine, Dendreon’s Provenge for prostate cancer, has reached the market, but many others have failed.

Dr. Chen said PD-1 could help explain those failures. Even though many of the vaccines did spur an immune response, that response was then snuffed out at the site of the tumor by PD-1. He said that using a PD-1 blocking drug along with a vaccine might prove a fruitful approach that should be explored.

Source: New York Times