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Originally published April 24, 2010 at 10:01 PM | Page modified May 5, 2010 at 2:18 PM

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Seattle biotech firm on verge of a groundbreaking cancer vaccine

A prostate-cancer treatment, if approved this week, could launch a whole new way to battle tumors — by firing up the body's natural defenses.

Seattle Times science reporter

Dendreon

• Founded in 1992 in Mountain View, Calif.

• Moved to Seattle in 1998

• 600 employees

• Other products in development include vaccines for bladder, breast, ovarian and colon cancer

• R&D and management based in Seattle

• Manufacturing plants in New Jersey, Georgia and California

Timeline

1998: Seattle becomes new headquarters of Dendreon, latest biotech company of Christopher Henney, co-founder of Immunex and Icos.

2000: Dendreon completes initial public stock offering of 4.5 million shares at $10 each. Shares end first day at $9.69.

January 2002: Early data from late-stage Provenge clinical trial shows it's "possible, but not probable" it will achieve safety and effectiveness goals, Dendreon says. Stock falls 38 percent that day.

May 2002: FDA halts patient enrollment in a second Provenge trial pending more information about the genetically engineered protein it uses.

August 2002: First clinical trial falls short of goal in patients with the most aggressive tumors, but shows significant benefits for the majority of patients who have run out of other treatment options.

October 2002: FDA allows restart of second Provenge clinical trial. Dr. Mitchell Gold promoted from chief business officer to CEO.

September 2003: Dendreon wins "Fast Track" designation to speed FDA's review of Provenge.

November 2005: Combined results of two clinical trials involving 147 men show 33 percent of those who got Provenge were alive three years later, compared with 15 percent of men who didn't.

November 2006: Dendreon completes FDA application seeking approval to market Provenge.

May 2007: FDA says more data is needed to support Provenge's effectiveness claims. Shares plunge 65 percent in a day, and Dendreon cuts work force by 15 percent. In following months, patients seeking the drug mount protests at FDA and file lawsuits.

April 2009: Dendreon says a 512-man clinical trial showed Provenge extended patients' median survival time by 4.1 months, setting stage for renewed FDA review. Company begins expansion of New Jersey processing center that makes Provenge, and later starts work on two more plants in Atlanta and San Diego.

November 2009: Dendreon completes FDA filing for Provenge, says the agency will issue its decision by May 1.

Sources: Seattle Times archives, Bloomberg

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Today's cancer-fighting tool kit consists mainly of the same trio of options as 50 years ago: Slash, burn and poison.

A Seattle biotech company appears poised to add a fourth.

A decision is due this week on Dendreon's application to bring the country's first cancer-treatment vaccine to market.

If the U.S. Food and Drug Administration (FDA) gives the expected green light, it will mark Seattle's biggest biotech breakthrough in nearly a decade. Dendreon's prostate-cancer treatment, called Provenge, leaps beyond the blunt instruments of surgery, radiation and chemotherapy to mobilize patients' own immune systems against their tumors.

The treatment's benefits are modest. But as the first product of its type to emerge from decades of often-frustrating research, Provenge could help open doors for immune-based therapies against a range of cancers.

"It gives me a lot of hope," said University of Washington researcher Dr. Nora Disis, who started chasing cancer vaccines at a time when many considered it folly. "I think the Dendreon vaccine will be the first in a long line we'll see approved over the next eight years or so."

Analysts estimate a course of Provenge will cost between $50,000 and $75,000. As many as 100,000 men a year develop the advanced form of prostate cancer the treatment would initially be prescribed for.

At that rate, Dendreon could rack up well over $1 billion in annual sales in a few years, said David Miller, president of Biotech Stock Research in Seattle. If the company isn't swallowed up by a pharmaceutical firm — a big "if" — its success would boost the region's stature and draw as a biotech hub.

"Dendreon does have the opportunity to become that anchor tenant," said Chris Rivera, president of Washington Biotechnology and Biomedical Association.

The fact the company has nothing yet to sell hasn't dissuaded investors. The value of Dendreon's stock exceeds $5 billion, making the company worth more than three times as much as Alaska Airlines — at least on paper.

But euphoria is risky in cancer research, cautions Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society. Drugs that seem like a slam-dunk for approval can be blindsided by an unfavorable decision from the feds.

Some live longer

Dendreon's case rests largely on a study of more than 500 men with an advanced form of prostate cancer that spread to other parts of their bodies. Of the men who got Provenge, nearly a third were still alive in three years, compared with less than a quarter of those who got placebos. The vaccine boosted median survival time by 4 months, from 22 months in the placebo group to 26 months in the Provenge group.

That may not sound like much, but it's significant for a group of men with few options, said Dr. Celestia Higano, a prostate specialist at Seattle Cancer Care Alliance who helped oversee the clinical trials. All doctors can now offer men in this stage of the disease is an extended course of chemotherapy that leaves most patients feeling wretched.

Retired Boeing manager Bob Feutz, who participated in the Provenge trial in 2007, said his worst side effects were chills and stiffness that went away in less than an hour.

Feutz was diagnosed with prostate cancer in 1996. Radiation knocked the disease into remission for several years. But the cancer returned and spread to his bones.

Three years after his Provenge treatment, Feutz' scans show no signs of relapse or metastasis.

"I'm comfortable that it's tucked away for a while," said Feutz, 84. "Now if I can keep it there for another 15 years, I'll be in good shape — and I'll be almost 100," he added, laughing.

Prostate cancer strikes nearly 200,000 American men every year and kills 27,000.

Experimental vaccines for melanoma, lymphoma and another approach to prostate cancer have shown survival benefits similar to Provenge, and could be close to approval, said Jeffrey Schlom, a vaccine expert at the National Cancer Institute.

"This has been seen in trial after trial now," Schlom said. "Patients are living longer, with a good quality of life."

More than 100 clinical trials are under way on cancer-treatment vaccines. Most are in the early stages, but more than a dozen have reached the final round before approval.

"I think we have to be cautiously optimistic," Higano said. "I don't see 20 immune therapies roaring down the highway at us right now, but I do see several."

Century-old idea

A few cancer vaccines are already on the market. They work like traditional vaccines to prevent infection with viruses that can cause cervical and liver cancer.

Cancer-treatment vaccines take an entirely different tack: revving up the immune systems of people who already have tumors.

The idea dates back more than a century. A New York bone doctor in the late 1890s noticed that cancer patients who suffered post-surgical infections seemed to do better — possibly because their immune systems were on high alert.

The earliest cancer vaccines were modeled on preventive vaccines, which use inactivated viruses and bacteria, or bits thereof, to prime the immune system to fight future infections.

Oncologists ground up tumors and injected patients with the slurry. When that didn't work, they tried whole tumor cells.

"It was kind of like the early attempts at rockets, where you see these things going up 10 feet, then crashing down," Schlom said.

Skeptics pointed out that the immune system evolved to fend off foreign invaders. Mutant though they may be, cancer cells are not foreign. The immune system recognizes tumors as "self" and holds back its big guns.

"The immune system sees the tumor more as something abnormal that has to be healed," said Disis, the UW researcher. "It doesn't see it as something dangerous that has to be destroyed."

The goal of cancer vaccines is to change that response.

"You want to create that danger signal," Disis said.

Retraining cells

Vaccine developers attempt to train the immune system to respond to protein targets, called antigens, on the surface of cancer cells.

Initially, scientists were nervous about this approach. While cancer cells often have abnormally high amounts of some surface proteins, including those that regulate cell growth and reproduction, most of those proteins also occur in healthy tissues.

But collateral damage hasn't been a major problem so far, said Schlom, of the National Cancer Institute. More vexing is that the immune responses elicited are often too tepid to make much of a dent in the malignancy.

The Dendreon vaccine incorporates an immune-booster to help kick the system into overdrive. The target is an antigen called PAP, which studs the surface of prostate-cancer cells.

Each dose of vaccine is personalized, making the production process a laborious one.

It starts with a three-hour, dialysislike procedure that plucks from the patient's blood potent immune cells, including the dendritic cells that gave Dendreon its name.

"It's painless, but boring," Feutz recalled. "I watched 'Forrest Gump' on the TV."

The cells are then "steeped" for several days in a broth rich with the PAP antigens.

When they come in contact with the antigens, the dendritic and other immune cells jolt into action. They gobble up the PAP proteins and embed some of them into their own surface membranes, like warning flags.

The activated immune cells are infused back into the patient in three doses, spread over a month. Once back on their home turf, they act as sentries to transmit the danger signal to T-cells, the combat troops of immunity. Relentless as Terminators, the T-cells search out and destroy their target: the prostate cancer.

But the outcomes in the Provenge study were far from perfect. Many of the men died from their cancer.

Daunting setbacks

The roll call of failures and frustrations in cancer immunotherapy is long. Xcyte Therapies, a former Seattle rising star, folded in the face of FDA concerns about its study design. Several other companies were shocked to discover their treatments made patients worse. Seattle-based Oncothyreon and its partner temporarily suspended trials last month on the immune-therapy drug Stimuvax after one patient developed brain inflammation.

Dendreon's low point came in 2007. Expecting FDA approval, the company was instead sent back to the drawing board. Angry prostate-cancer patients and advocates rallied outside FDA headquarters.

The setback added another three years to the 15 Dendreon already had spent on Provenge. The amount of money plowed into the project is now close to $750 million.

"It shouldn't have taken this long," said Stanford University professor Dr. Edgar Engleman. "I think the world wasn't quite ready for such a novel approach."

Those are the words of a proud parent.

Though no longer associated with Dendreon, Engleman was one of the scientists who founded the company in California in 1992. Dendreon moved to its current Seattle headquarters, overlooking Olympic Sculpture Park, in 1998.

Company officials declined to be interviewed in advance of the FDA's decision.

But their actions bespeak confidence. Dendreon's work force has ballooned from 200 to 600 this year. Another 150 openings are listed on its website.

Many of the new jobs are in New Jersey, where Provenge will be initially manufactured. The company is also building plants near Atlanta and in Orange County, Calif.

While the projected price of Provenge seems as though it might induce sticker shock, it's not out of line with other new cancer treatments, said Miller, the biotech analyst. Prostate cancer mostly strikes older men, and Medicare covers all FDA-approved drugs. Insurance companies usually follow suit, Miller said.

But even if Provenge is a smash, it's not clear how much that will mean for Seattle.

The city has watched its other big biotech winners, like Immunex and Icos, get snatched away by drug companies, Miller pointed out.

"That is the life cycle for most biotechs," he said. "They don't grow up to be Pfizer. They grow up to be bought by Pfizer."

Heading off relapses

Cancer-vaccine studies have focused mainly on the sickest patients — those whose disease has metastasized and resisted other treatments.

But the real power of immune therapy may lie in treating relatively healthy people whose tumors have been cut out or knocked into remission by radiation or chemotherapy, Schlom said. While they may appear free of disease, a few stray cells can be enough to cause a relapse years down the road.

Cancer vaccines are, in theory, ideally suited to perform mop-up duty, he said.

Trials to test that prospect are already under way with Provenge and other vaccines. But studies that measure long-term survival can take five to 10 years to reach conclusions.

Meanwhile, the science has advanced beyond Provenge's single-antigen formula to experimental vaccines that coax the immune system to attack multiple targets on cancer cells, Disis said. She and others are also working on what might be the ultimate vaccine: one that prevents cancer from developing in people who are genetically predisposed to the disease.

Scientists agree that's a long way off.

"There are a lot of things about the immune system we still don't understand," Higano said. "Provenge is a great step forward, but it's just the first baby step."

Sandi Doughton: 206-464-2491 or sdoughton@seattletimes.com

This story was originally posted April 24 and updated April 26. The May 2007 entry in the timeline originally noted that an FDA panel of experts said more data was needed to support Provenge's effectiveness claims. It was the FDA that said that, however.


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