Insight: Training immune system to fight cancer comes of age
NEW YORK 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."
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.
"Yervoy in combination with the proper vaccine could do phenomenal things," predicted Armen. "You'll be looking at cures and long-term survival."
Yervoy is being tested with Roche's new Zelboraf, which targets melanoma in patients with a specific gene mutation.
"Zelboraf had a high response rate but doesn't last that long," said Dr Patrick Hwu, chairman of the melanoma department at MD Anderson Cancer Center in Houston. "With Yervoy we have a lower response rate but some patients are essentially cured. By combining them, it's possible we can get a high response rate that's durable."
This optimism must be tempered by the skyrocketing price for such treatments, which are likely to further tax healthcare budgets. Yervoy costs about $120,000 for a course of treatment, while Zelboraf costs about $56,000. Wolchok is working on ways to identify the patients most likely to gain the sustained life-extending benefit from Yervoy.
The science behind Yervoy is based on the discovery in the 1990s of a molecule called CTLA-4 that works as an immune system braking mechanism to keep it from attacking healthy tissue.
"Our immune cells are like little tanks that travel round the body to shoot bacteria and viruses that are hurting us, but you can't let them go unregulated," said Hwu. "When the body has cancer we want the tanks to go a little bit wild, so we want to lift those brakes and let them go after the enemy."
The inhibition of another immune-system braking mechanism called PD-1 being tested by Bristol-Myers, Merck and others is also considered a promising avenue of attacking solid tumors, doctors said.
THE VACCINE OPTION
Therapeutic vaccines work a little differently. Whereas drugs like Yervoy manipulate mechanisms of the immune system, vaccines tend to activate or boost the patient's anti-tumor immune response to more efficiently go after cancer.
"The key with these vaccines is there is minimal toxicity and increased survival. This is just what patients want - good quality of life," NCI's Schlom said. "The immune system is keeping the tumor in check. It's not a poison."
To get investors on board, cancer vaccines will likely need a champion to help erase skepticism in the field.
Some 16 percent of Oncothyreon Inc shares are being shorted by investors who are betting its Stimuvax lung cancer vaccine will fail. They are wary after independent monitors said the drug should continue to be studied in a pivotal trial that could have been halted on clear signs of success.
Michael Becker, president of MD Becker Partners consulting firm, said the message he gets from investors when it comes to immunotherapy companies is that "they are on the sidelines ... and will remain so until there is another victory in the field."
A victory with the potential to change investor perception and alter clinical practice could come from Bavarian Nordic's Prostvac for prostate cancer, which NCI's Schlom cited as one of the most promising in the field.
Originally developed by NCI, Prostvac is a virus-based vaccine that in Phase II trials showed an average 8.5 month overall survival benefit, more than double that of Provenge.
"If the results in the large study confirm the earlier studies, that would be a very significant advance," Dranoff said.
BIG SPENDERS ARE IN
Where the field was once largely left to small biotechs, the approval of Yervoy and other scientific advances have brought the industry's big players on board.
In the last year, Amgen Inc spent more than $1.5 billion to buy two companies with promising cancer immunotherapy portfolios, one of them a vaccine program.
"It is engineered to use the tumor's cellular machinery to replicate itself and ultimately cause local destruction of the tumor," said Amgen's chief medical officer, Mike Severino.
In a display of confidence in its vaccine program, Glaxo recently paid Agenus $9 million, $2.5 million of which was to be credited against future royalty payments.
Anderson's Hwu is impressed by Agenus's drug adjuvant, which adds firepower to Glaxo vaccines by activating a key component of the immune system called dendritic cells. "They tell the immune cells to get off the couch and go in there and kill some tumors," Hwu said.
Marc Engelsgjerd, a senior analyst for Wolters Kluwer inThought, believes companies would do well to test immunotherapies at an earlier stage of the disease, perhaps to prevent recurrence. Such trials take years longer to produce results, so companies tend to start trials with advanced cancer patients with limited life expectancy that yield results sooner.
The body's immune system is constantly trying to keep tumors from forming or coming back, he said. "If you can give the immune system a boost in terms of helping out with that long-term surveillance, that to me makes more sense biologically."
Engelsgjerd favors Neuvax, a breast cancer vaccine being developed by Galena Biopharma that is intended for earlier-stage use following surgery.
The immune system may take some months to ratchet up its anti-cancer armaments researchers said, so giving immunotherapy to a patient with just a few months to live may be futile.
Schlom agrees that early disappointment in the field may have been due to testing on patients with very advanced disease whose immune systems were severely compromised by chemotherapy and radiation, but he said such failures are to be expected.
"This is a pivotal time for sure, but it's not because we just got smarter in the last year," Hwu said. "It's because people have been working very hard."
(Additional reporting by Julie Steenhuysen in Chicago; Editing by Michele Gershberg, Martin Howell and Prudence Crowther)
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