Immune checkpoint blockers show promise against melanoma

When Janelle Robinson used a hair-removal kit from the Home Shopping Network, all she wanted to remove from her birthmark was hair. Three months later, she learned there was something else to remove: melanoma.

It spread throughout her left leg, even after four surgeries. Then in March, Robinson joined a clinical trial for the drug lambrolizumab; since then, her tumors have nearly disappeared.

"Words can't even express what I felt," Robinson said. "I knew my blessing was coming. I just didn't know when."

Lambrolizumab is just one "immune checkpoint blocker" in the new class of drugs that are revolutionizing melanoma therapy. Two papers published in June in the New England Journal of Medicine showed they reduce tumor sizes and lengthen survival of patients with advanced melanoma. Larger studies are underway throughout Philadelphia.

The American Cancer Society predicts that this year, 9,480 people in the United States will die of melanoma, a condition in which skin cells providing color multiply out of control.

Checkpoint blockers make cancer the roadkill of immune systems. "Imagine a car at the top of the hill that you want to make go," said Robert Vonderheide, an oncologist at the University of Pennsylvania's Abramson Cancer Center. "You have two options. Either press the gas pedal or release the brakes. These drugs are designed to cut the brakes as a way of getting the immune system to move."

Each drug releases one of many brakes on immune cells. Lambrolizumab releases the PD-1 brake. Tumors got smaller in 38 percent of those who received intravenous injections. Nivolumab, which releases the same brake, shrank tumors in up to 40 percent of patients when given with a drug called ipilimumab.

"This is going to be a huge paradigm shift in the treatment of our patients," said Anthony Olszanski, director of early-drug development at Fox Chase Cancer Center.

Olszanski says chemotherapy was the mainstay of treatment for advanced melanoma until 2011, when the FDA approved the first checkpoint blocker, ipilimumab. "But many of us felt that it was not good enough. And that's primarily because the response rate was only about 15 percent," he said.

Because checkpoint blockers are not tumor-specific, they may have use in other cancers, said James Riley, a Penn immunologist and author of an editorial accompanying the two papers.

But caveats temper the promise of these drugs.

They may be effective only in late disease when the immune system has had a chance to respond. "Remember," Vonderheide said, "you have to be at the top of the hill to go down."

Side effects, including inflammatory reactions in the skin and gastrointestinal tract, were reported in up to 53 percent of patients.

More people need to be tested. One of the published studies had only 86 patients, while the other had 135.

Philadelphia is involved in at least seven clinical trials to further test immune checkpoint blockers.

"It's a little bit like Coke and Pepsi," Vonderheide said of the different drugs. "But you know how emotional people get about that. And not every drug is the same, even if they look similar molecularly."

What happens in a cell without its brakes? Why doesn't every patient respond? Can responders be identified by their genes? These are questions the clinical trials will address.

"I just think that the amount of new treatment options that have become available in the last two years is really impressive," said Tara Gangadhar, an oncologist who leads several clinical trials at Abramson.

For retired military officer David Bolgiano, one such trial saved his life. He was headed back to Afghanistan when his wife spotted a mole that grew into Stage IV melanoma. He was told to pick a hospice. But with ipilimumab, his tumors stabilized, and he's now back to riding his motorcycle.

"Everything in the media about cancer is gloom and doom," Bolgiano said. "But that's not so. I'm still here."