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Medicine to thwart cancer's protective cloak

By Gina Kolata | The New York Times | Updated: 2013-10-27 07:34

For more than a century, researchers were puzzled by the ability of cancer cells to evade the immune system. They knew cancer cells were grotesquely abnormal and should be killed by white blood cells. In petri dishes white blood cells could go on the attack against cancer cells. So why could cancers survive in the body?

The answer, when it came in recent years, arrived with a bonus: a way to thwart a cancer's strategy. Researchers discovered that cancers wrap themselves in an invisible protective shield. And they learned that they could break into that shield with the right drugs.

So far, the drugs have been tested and found to help patients with melanoma, kidney and lung cancer. In preliminary studies, they also appear to be effective in cancers of the breast, ovaries, colon, stomach, head and neck.

It is still early, and questions remain. Still, researchers think they are seeing the start of a new era in cancer medicine.

"Amazing," said Dr. Drew Pardoll, the immunotherapy research director at Johns Hopkins School of Medicine in Baltimore, Maryland. This period will be viewed as a moment in medical history when everything changed, he said.

The story of the new cancer treatments started with the discovery of how cancers evade attacks. It turned out that they use the body's own brakes, which normally shut down the immune system after it has done its job killing virus-infected cells.

One braking system uses a molecule, PD-1, on the surface of T-cells of the immune system. If a target cell has molecules known as PD-L1 or PD-L2 on its surface, the T-cell cannot attack it. So some cancer cells drape themselves in those molecules. The discovery led to an idea: Perhaps a drug that covered up any of those PD molecules would allow the immune system to do its job.

The first indication that a cancer's protective shield might be breached came in 2010, after a trial of the drug ipilimumab in patients with otherwise untreatable melanoma. Patients who took the drug survived an average of 10 months, or 4 months longer than those randomly assigned to a different treatment. About 20 percent of patients who responded have now survived up to 10 years.

"It was spectacular," said Dr. Axel Hoos of GlaxoSmithKline, who had helped develop the drug at Bristol-Myers Squibb.

The drug was approved for melanoma in March 2011, with a high price tag - $120,000 for a course of therapy. It had another drawback. By unleashing the immune system, it sometimes led to attacks on normal cells. But the trial was a proof of concept.

Dr. Suzanne Topalian, a professor of surgery and oncology at Johns Hopkins, was one of the first to test the new drugs in patients. The trial began in 2006, with 39 patients who got a PD-1 blocker, made by Medarex, since bought by Bristol-Myers Squibb.

The study looked at safety, not effectiveness. But one patient had a partial regression of her tumor.

That led to studies of two Bristol-Myers drugs: one that blocks PD-1 and another that blocks PD-L1. The studies included 503 patients with a variety of advanced cancers who had exhausted other options. The findings, presented in October 2012 at a meeting of the American Society of Clinical Oncology, were striking. A significant proportion of patients responded, including 18 percent of 76 lung cancer patients who got the PD-1 drug and 10 percent of 49 who got PD-L1 drug. Dr. Pardoll, who is married to Dr. Topalian, said that when she and her colleagues presented the data, "it was almost like a hush fell over the room: 'Can this really be?'"

Researchers are heartened by those few whose cancers were halted by the drugs, but caution that these patients are unusual.

"What you really want to know," said Dr. Roger M. Perlmutter, the president of Merck Research Laboratories, "is, are people living longer?" For that, "you just have to wait," he said, adding, "What I don't want to do is give people false hope."

But some patients, like two treated at Johns Hopkins, have become emblems of hope.

In 2007, M. Dennis Sisolak, who is 72 and a retired engineer from Bel Air, Maryland, learned he had kidney cancer. The cancer had spread. After he tried two new drugs to no avail, his doctor, Dr. Charles G. Drake, a kidney cancer specialist at Johns Hopkins, enrolled him in an early phase clinical trial of a PD-1 inhibitor. His cancer disappeared on scans and has not returned, even though he has had no treatment for a year.

Dr. Drake said three of his patients had similar responses. All, with advanced disease, would have been dead by now, he said, adding, "I have never seen anything like this, personally."

David Gobin, 63, a retired Baltimore police officer, has a similar story. He learned he had lung cancer in 2008. He had surgery to remove part of his right lung, then radiation and chemotherapy. Two years later, the cancer was back, and it had spread. He had more surgery, more chemotherapy, more radiation.

In 2010, Mr. Gobin entered a clinical trial of an experimental drug that interferes with cell growth, but had no success. Then his doctor at Johns Hopkins suggested a Phase 1 trial of an anti-PD-1 drug. His tumors shrank significantly and have not grown, even though he stopped taking the drug eight months ago.

"I was in the right place at the right time," Mr. Gobin said. "I will always have cancer, but you know what, I can live with it."

The New York Times

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