Immune therapy lifts hopes in fight with cancer
Dr. Ronald Eckert was combing his hair when he noticed a hard lump on his head. It turned out to be melanoma and, despite multiple surgeries, tumors appeared in his lungs and liver within a year.
The Buffalo, N.Y., gastroenterologist was told he had six months to a year to live and he took a leave from his job to reckon with the grim prognosis. Then his wife, a nurse, tapped her social network and learned about a doctor in Boston who was running clinical trials of experimental drugs that might help.
In June 2012, Eckert went to Massachusetts General Hospital for his first infusion of a drug designed to release a brake the cancer was using to suppress his body’s immune system, and evade attack. Now almost two years later, the cancer has vanished and Eckert, 70, is back skiing, flyfishing, and golfing.
“To me it borders on the miraculous, really, because I’ve had no side effects whatsoever,” he said.
Eckert’s treatment exemplifies a shift in the scientific strategy for fighting some cancers. Driven by fundamental research — much of it done in Boston — an immune therapy approach that was on the fringes of cancer therapy is suddenly the hottest trend in cancer drug development.
Last week, for example, Boston researchers presented data showing that nearly half of patients with advanced melanoma lived for two years after getting an experimental immune therapy called nivolumab, though multiple other therapies hadn’t worked for them. Last month, the Swiss drug company Novartis AG acquired immunotherapy company CoStim Pharmaceuticals in Cambridge for an undisclosed amount. And Agenus Inc. in Lexington recently announced it had acquired 4-Antibody AG, a European firm focused on developing immune-stimulating therapies.
The frenzy of activity is an abrupt change for a field that had made big promises but failed to deliver for years; researchers searching for ways to spark an immune system attack on cancer felt like they were in a small club of believers.
The insight that finally helped cancer immunotherapy gain traction was that there was more than one way to attack the problem. Many efforts had been made to rev up the immune system, the body’s natural defense against pathogens, so that it would seek and destroy cancer with greater ferocity. But the molecules that regulate the immune system are complex, and there are a number of natural switches that act like brakes — suppressing it so that it doesn’t attack the body’s own cells. Those brakes may also keep the immune system from going after tumor cells.
What if, some researchers wondered, instead of gunning the engines, they could find a way to block the brakes?
In the 1990s, researchers debated whether a molecule found on the surface of immune cells called CTLA-4 was a suppressor of the immune system or a trigger. Arlene Sharpe, a professor of microbiology and immunology at Harvard Medical School, engineered a mouse lacking the gene in 1995. With the gene knocked out of the mice, it looked as if their immune systems were attacking their own cells; they died at three weeks of age. CTLA-4 was clearly a brake.
The following year, James Allison, a scientist who now works at MD Anderson Cancer Center in Houston, found a way to release the brake by blocking CTLA-4, and showed that it enabled the immune system to go after tumors. In a clinical trial led by Dr. F. Stephen Hodi at Dana-Farber, an experimental CTLA-4-blocking drug made headway in a subset of patients with melanoma, a cancer that hadn’t seen progress in years.
But there were some significant side effects to the drug, and it seemed to be specific to skin cancer. But such problems would soon be addressed by the potent effects of a powerful class of drugs developed partly based on insights from another Boston laboratory.
Building on discoveries by a Japanese scientist, Gordon Freeman at Dana-Farber led work in the early 2000s to identify two molecules that bind to a protein called PD-1 and signal the immune system to stand down.
An early decision by the Boston researchers to license that key discovery nonexclusively has led to more than a half-dozen pharmaceutical companies racing to create products in this one class of drugs.
“We decided to just put the idea out there, and say this would be a good thing to develop and anyone who wants to develop it can,” Freeman said. “And the drug companies really picked up on the idea and have done fabulous jobs.”
The approach is now working in an unexpected variety of cancers, such as a subset of lung and kidney cancer patients. Although the data are still early, the responses appear to be long-lasting — as with the melanoma patients treated with a PD-1 blocking drug, which Hodi and colleagues reported on Monday in the Journal of Clinical Oncology.
“These [PD-1 blocking] drugs are basically already on the map,” said Dr. Keith Flaherty, a melanoma specialist at Massachusetts General Hospital Cancer Center who has been treating Eckert. “Not one of them is FDA-approved yet, but we have seen enough evidence in our patient trials to say this is a quantum leap.”
The strong results may lead to immunotherapy’s next chapter. Flaherty has been a pioneer in using targeted therapies matched to the genetic characteristics of a patient’s tumor, medications that have stirred great excitement but that almost inevitably fail eventually, when patients develop resistance to the drugs.
He is now collaborating with immunology researchers to try to understand whether targeted drugs and immunotherapies may be more effective when combined. Clinical trials are testing such combinations, and Flaherty and colleagues are exploring how genetically targeted therapies may change the vulnerability of a cancer to an attack by the immune system. They already have found that if they administer a genetically targeted melanoma treatment to biopsies taken from a patient, immune cells attack the cancer cells more vigorously.
“Suddenly there’s credibility to this whole field of cancer immunology,” Harvard’s Sharpe said. “That’s been a landscape change.”