Training immune system to fight cancer comes of age

NEW YORK, (Reuters) – More than 100 years after researchers first explored the potential to harness the body’s immune system to fight cancer, the field’s leading doctors see the concept finally proving itself on a large scale in the next year or two.

Two drugs based on immunotherapy are already available and have met with mixed results. Bristol-Myers Squibb’s Yervoy has been hailed as a major breakthrough for treatment of melanoma since its approval last year, while Dendreon Corp’s Provenge prostate cancer vaccine has been hampered by management missteps and doctors’ reluctance to adopt the difficult-to-administer therapy after two years on the market.

They are viewed as harbingers of a treatment revolution that could gain a significant share of the global market for oncology drugs, estimated by IMS Health to reach $75 billion by 2015. Scores of new immunotherapy vaccines and other immune system modifiers are being tested against a variety of cancers.

“We have entered into a new era where immune therapies can be recognized as an important component of cancer treatment,” said Dr Glenn Dranoff, co-director of the Dana-Farber Cancer Vaccine Center in Boston. “There’s certainly more excitement and more confidence in the field than there ever has been before.”

At least a dozen therapies are set to have key late- or mid-stage trial data over the next 12 months, and some experts believe the results will be a tipping point for the field as clinical successes pile up.

“Several of these are going to (succeed). Once they get approved by the FDA, they will be used more and more,” said Jeffrey Schlom, chief of the National Cancer Institute’s (NCI) Laboratory of Tumor Immunology and Biology.

Among anticipated new treatments are a prostate cancer vaccine from Denmark’s Bavarian Nordic, a lung cancer vaccine from GlaxoSmithKline and one for melanoma from Amgen. Others in advanced testing of such therapies include Vical Inc and NewLink Genetics.

Investors spooked by years of past failure in the field may want to take note of the enthusiasm from the medical community. Some say Wall Street has taken Dendreon’s disappointing sales as an indicator of the prospects for other research.

“Investors would do well to look away from Dendreon and to companies pouring money into the field,” said Dr Jedd Wolchok, director of immunotherapy clinical trials at Memorial Sloan-Kettering Cancer Center in New York. He cited Merck , Roche’s Genentech and AstraZeneca’s MedImmune units as among those companies. “Nothing begets investor confidence like a little bit of success,” he said.

A new benchmark?

The concept of using the immune system against cancer dates back to the 1890s when Dr. William Coley, a New York surgeon, noted that some patients who got infections after cancer surgery fared better. He surmised that the immune response triggered by the infection was also working to eradicate cancer.

“Although the idea of a vaccine or cancer immunotherapy has been around really for at least 100 years, we now know a lot more about what are the requirements to generate an effective anti-cancer immune response than we ever did,” Dranoff said.

The new understanding of how immunotherapies work may demand a revised definition of clinical success.

While extending life is the gold standard, most cancer drug trials have been deemed successful if tumors shrink or if a treatment can demonstrate a delay in tumor growth or in worsening of the disease, known as progression-free survival (PFS).

But Provenge and Yervoy have extended survival without necessarily impacting PFS or tumor shrinkage in many cases.

“Overall survival is the accurate indicator. Tumors may look bigger because they are filled with immune cells, so they appear worse,” said Wolchok. “We’ve proposed a new set of response criteria to try to incorporate some of this biology.”

Yervoy, or ipilimumab, became the first drug ever to extend survival in patients with advanced melanoma, long seen as a short-term death sentence. On average, it added only about four months of life in pivotal trials, although some 20 percent of patients had an impressively durable response to the drug.

“We have patients who are (alive) now nine years. That’s what’s really the most convincing evidence for clinically meaningful tumor destruction by the immune system,” said Dranoff.

Oncologists have referred to such patients as essentially cured, although Wolchok was reluctant to do so.

“There are some people who we have treated with ipilimumab whose scans look just as abnormal now as they did five years ago, so it has turned it into a chronic disease,” Wolchok said. “It changed the situation from something they were dying from into something they are living with. That really does show you that the immune system can restore an equilibrium between the person and the tumor.”

New combinations

Researchers had previously believed that only melanoma and kidney cancer had the right properties to respond to immune system therapy. They were delighted to be proved wrong. Clinical trials now are taking on lung, breast, liver, prostate, pancreatic, ovarian, head and neck and brain cancers.

“This is a revolution that has gotten started, and I think the next few years will tell the story,” said Garo Armen, chief executive of Agenus Inc, which makes the QS-21 adjuvant, a drug used to boost the immune response to Glaxo’s experimental vaccines for lung cancer and melanoma.

The basic idea remains the same – train a patient’s immune system to attack the cancer. But new approaches based on more recent knowledge of the immune system’s components include activating a variety of cells to go after tumors and modifying mechanisms that keep either the immune system in check or turn it loose.

There appears to be near universal agreement that to achieve optimal benefit, immunotherapies should be combined with targeted cancer drugs or other immunotherapies in a multi-pronged attack.