Analysis: New drugs teach immune system to kill cancer

CHICAGO (Reuters) - Bristol-Myers’ experimental drug ipilimumab is the first to extend lives in patients with advanced melanoma, and its success heralds a new era of cancer “immunotherapy” -- drugs that enlist the help of the immune system to fight the disease, researchers said on Saturday.

Ipilimumab or “ipi” is a monoclonal antibody, an engineered version of a human protein that targets CTLA-4, a molecule that acts like a brake on the immune system.

By gumming up that brake, the drug unleashes the immune system to seek and destroy tumors.

“This is just the beginning. We’re changing the view of how we can manipulate the immune system to fight cancer in people,” said Dr. Stephen Hodi of the Dana-Farber Cancer Institute in Boston, whose study on ipilimumab appears in the New England Journal of Medicine.

More than 20 percent of patients with advanced melanoma, the deadliest form of skin cancer, were alive two years after getting the drug -- compared to a usual nine months.

Some have lived more than four years after receiving the drug, which is being tested in lung cancer as well. If approved by regulators, the Bristol-Myers Squibb BMY.N drug could have sales of $425 million by 2014, according to Thomson Pharma.


Earlier this year, the U.S. Food and Drug Administration approved Dendreon Corp's DNDN.O Provenge, a therapeutic vaccine designed to stimulate the immune system to attack prostate cancer.

“This year heralds, I think, the beginning of real immunotherapy in cancer,” said Dr. Philip Kantoff of Dana-Farber, who led the largest clinical trial for Provenge.

Kantoff said for many years researchers have been trying to prove it is possible to get the immune system to fight cancer.

“Most of what exists up to now have been anecdotes and no real definitive studies,” he said.

For a small fraction of patients, immunotherapy can bring a complete reprieve from their cancer. But many patients do not respond this way, or at all, and researchers are looking to combine drugs like ipilimumab with other compounds with the hope that more patients will benefit.

“The next big emphasis will be trying to predict up front the 20 to 30 percent of patients who seem to be doing so well with this drug and putting this drug in combinations with other drugs,” said Dr. Steven O’Day of the Angeles Clinic and Research Institute in Santa Monica, California, who presented the ipilimumab findings to media on Saturday at the American Society of Clinical Oncology meeting in Chicago.

The goal would be to see 50 percent or more of patients getting some benefit, O’Day said.


Several clinical trials are under way testing ipilimumab in combination with pills that target cancer-causing mutations of the BRAF gene, which occur in 50 percent to 60 percent of melanoma patients.

These drugs include PLX4032, which Roche ROG.VX is developing with privately held U.S. biotech company Plexxikon, and a BRAF inhibitor that has shown promise in early stage testing by GlaxoSmithKline GSK.L.

Ipilimumab is also being tested in combination with chemotherapy and antiangiogenesis drugs, such as Roche’s Avastin, a $5 billion-a-year seller in colon, lung and breast cancer that chokes off blood flow to tumors. In a study last September led by O’Day, Avastin fell just shy of showing a benefit in patients with advanced melanoma.

Kantoff said there are several other molecules in the body besides CTLA-4 that dampen the immune system. Antibody drugs that target two of these -- CD-137 and PD-1 -- are already under development at Bristol-Myers.

Success in these trials will mean learning what it looks like when the drug works, researchers say.

Dr. Anna Pavlick, director of the melanoma program at New York University’s Langone Medical Center, said in some cases, patients treated with ipilimumab looked like they were getting worse on CT scans.

“What you are seeing is an inflammatory response on your CT scans,” Pavlick said. “You have to look at your patient. If the patient looks good and the scan looks bad, you keep going.”

That can be difficult for cancer doctors, who use tumor size as one measure of success.

“We’re trained as oncologists to say if things don’t shrink on the CT scan, it’s not a successful therapy. We find with these kinds of agents, that is not necessarily true.”

This raises questions about how best to structure clinical trials for immunotherapy drugs, and it may raise hopes for Pfizer Inc's PFE.N tremelimumab, another monoclonal antibody that targets CTLA-4, Hodi said.

Two years ago, that drug failed in a large study comparing it to chemotherapy. Earlier this year, Pfizer signed a deal to co-develop the drug with Debiopharm Group using a biomarker to pick patients most likely to respond.

“It offers hope for not just that drug but for many others,” Hodi said.

Editing by Doina Chiacu