Avax Technologies Prepares to Sell Personalized Skin-Cancer Vaccines

Avax Techologies Inc. said it will begin selling a personalized skin-cancer vaccine in Australia, in one of the first moves to market medicines customized to individual users.

¹Tailor-Made Cancer Vaccines Show Promise in Early Trials (Nov. 18)

The Kansas City, Mo., company's vaccine will be one of the first cancer vaccines of any type to reach commercialization. Such treatments, under study for decades, aim to stimulate patients' immune systems to reject the cancer as foreign. Although called vaccines, generally they are given to treat existing cancer, rather than prevent it. Many of the ones under study are "off the shelf," which means they are made from one patient and mass-produced for widespread use.

But Avax's skin-cancer vaccine is made from patients' own tumors, which could theoretically be more powerful because each person's cancer is different. Indeed, such personalized nostrums have shown early promise in several types of cancer.

Skeptics have argued that it is impractical and prohibitively expensive to concoct a different vaccine for each patient. "No one really believed that we'd be able to do this," said Avax Chief Executive Jeffrey Jonas.

It won't be easy -- or cheap. The vaccine is for melanoma, a serious type of skin cancer, and is intended only for those whose cancer has already spread to other locations, such as the liver or kidney. After the patient's tumor is removed surgically, it will be shipped on ice to Avax. The company uses radiation to kill the cells, then alters them chemically to make them more recognizable to the patient's immune system as foreign; it then ships the finished vaccine to the doctor performing the injection.

The cost for the standard form of the treatment, which includes weekly shots for six weeks and a booster shot six months later, is expected to be about $10,000 to $15,000.

Avax has yet to gain coverage of the drug from the Australian government's nationalized health-care system, which will rigorously scrutinize its efficacy data. However, the government is allowing the vaccine to be sold under a national law that allows the sale of personalized treatments without a formal efficacy review. All that is needed is government certification that its manufacturing facilities meet standards -- a hurdle Avax passed recently.

As of 4 p.m. on the Nasdaq Stock Market Monday, Avax was trading at $9.6875, down 37.50 cents.

The company is in the midst of final-stage clinical trials on its vaccine, and hopes to apply to the U.S. Food and Drug Administration by 2003.

Page One Feature

Tailor-Made Cancer Vaccines
Show Promise in Early Trials

The lemon-sized tumor on Dallas Dillon's liver was supposed to have killed him by now. Instead, it was used to make a drug that may save his life.

Last year, a Houston surgeon removed the tumor -- Mr. Dillon's fourth since 1994 -- and shipped it on dry ice to a Massachusetts lab. There, it was made into a vaccine that doctors hope will "teach my body to fight the cancer," says the 37-year-old former construction worker.

The quest for a cancer vaccine has been under way for years, of course. But Mr. Dillon is part of an unusual and controversial offshoot: the effort to develop custom-made vaccines. At least six companies, including Antigenics LLC, which supplies Mr. Dillon's drug, are conducting human trials of personalized vaccines for skin, kidney, breast and other cancers.

Though far from conclusive, the early results have been promising. And the vaccines, whose main ingredients come from a patient's own cells, have produced no side effects. "Compared to chemotherapy, this was paradise," says James Stewart Nagle, 59, who began receiving an Antigenics melanoma vaccine in March and now shows no sign of cancer.

However, skeptics say that even if further trials prove the new therapies effective, they will be prohibitively expensive. Moreover, their developers might never standardize manufacturing practices enough to satisfy Food and Drug Administration regulators. That's because the results can vary according to the particular tumor's characteristics -- it may be hard or soft, for example, littered with dead tissue or caked with bacteria. "The approach is not reproducible enough or standardized enough that it can ever become a marketed product," says Drew Pardoll, an oncology professor at Johns Hopkins University School of Medicine.

Certainly, it won't be easy. Intracel Corp. in January published data in the British medical journal the Lancet showing its vaccines substantially reduced the recurrence of colon cancer for five years after treatment. But the Rockville, Md., company is still trying to figure out how to make a commercial-quality product. At the FDA's behest, it has postponed seeking marketing approval while it retools its manufacturing process to fix a bacterial-contamination problem.

"This is not the standard therapeutic approach where you just make it in a vat," says Michael G. Hanna Jr., Intracel's chief executive. And, except for blood-transfusion products, the FDA so far has approved only one personalized therapy of any kind, a knee-repair goo grown from a patient's own cartilage.

Though patients who take part in the cancer-vaccine trials get their drugs free of charge, many in the medical community fear that commercial versions of the patient-specific formulas would be too costly for any but the richest or best-insured.

Alex McPherson, CEO of Canada's Biomira Inc., estimates that such vaccines would cost patients $10,000 to $50,000 per course of treatment --roughly 10 times the range of what mass-produced cancer vaccines would probably bring if any were to be approved for marketing. A lymphoma treatment Biomira now has in clinical trials originally cost as much as $80,000 a patient to make, but Dr. McPherson says the company has since cut production costs "significantly."

Antigenics, which is based in New York, began testing its vaccines in humans in 1997 at New York's Memorial Sloan-Kettering Cancer Center. Company co-founder Pramod K. Srivastava, now a professor of immunology at the University of Connecticut, laid the groundwork for the trial as a graduate student in the early 1980s. Experimenting on rats, he discovered that heat-shock proteins, so named because they help cells repair heat damage, showed promise as cancer vaccines. The proteins, he says, cling to many tumor-cell components, providing a crib sheet that shows the body what to fight.

¹AstraZeneca Researchers and Others Progress on Hard-to-Treat Cancers (Nov. 17)

But the Sloan-Kettering trial exposed some unexpected difficulties in turning heat-shock proteins into custom vaccines. It aimed to treat advanced pancreatic cancer, but Antigenics soon found that the pancreas's digestive juices break down the proteins. Antigenics was able to produce vaccine for only five of the 15 test subjects. Four of the five are still alive, including three who now show no evidence of cancer. The company is working to fix the production problem.

Antigenics had better luck with vaccine manufacture at M.D. Anderson Cancer Center in Houston, where it was able to produce vaccine for 38 of 42 kidney-cancer patients. A few weeks into the initial trial there, researchers were surprised to see some of the patients' tumors begin to shrink.

The grapefruit-size lump on the arm of one kidney-cancer patient in his 50s shrank to the size of a pea. Doctors had considered the man's condition hopeless, so they hadn't subjected him to surgery, but -- encouraged by his improvement -- they later removed his tumor; after subsequent vaccine injections he remains cancer-free. Robert Amato, the osteopath running the hospital's month-long trial, was so excited by its results that he extended it.

Meanwhile, several floors above, Mr. Dillon and dozens of other patients were receiving a vaccine for melanoma, a virulent form of skin cancer. The fair-complexioned father of three, who lives in Bethel, Ohio, had discovered an ugly mole on his right arm in 1991. It was removed. In 1994 and 1995, doctors found and removed tumors in his armpit and chest. In 1997, the cancer re-emerged in his groin and was again excised. In March 1998, yet another lump was discovered, on his liver. The doctor said further surgery was pointless, says Mr. Dillon's wife, Susan. Her husband was told he would probably die in six months to a year.

After a relative found M.D. Anderson via the Internet, the Dillons flew to Houston. At first, doctors there gave Mr. Dillon an experimental chemotherapy cocktail. His tumor began to shrink, but it started to grow again after he had taken the maximum dosage allowed in the trial. His doctors were reluctant to remove his tumor, sure that the cancer would simply recur elsewhere. But "I said it was coming out, even if I had to remove it myself," Ms. Dillon recalls.

Steven A. Curley, one of the hospital's leading surgeons, operated in December 1998, but some of the tumor tissue had to be left behind. Mr. Dillon got his first vaccine shots two months later. At a follow-up visit in March, a scan showed a new tumor the size of a quarter in his abdomen. But an April scan showed its growth had ceased.

By July, the Dillons were elated, but Mr. Dillon needed more injections. His hunting club raised $12,000 for the couple by throwing a pig roast to help finance more trips to Houston, which were averaging about $2,000 in air fare and hotel expenses.

In September, Mr. Dillon arrived for another battery of scans. In researcher Omar Eton's waiting room, nurse Mary Jo East flashed a jubilant thumbs-up. "It's good news!" she called out. His condition had stabilized.

Dr. Eton later warned Mr. Dillon that he couldn't promise the cancer wouldn't start growing again. In an interview, he says it appears that the vaccine is responsible for stabilizing Mr. Dillon's condition, but he adds that there is no proof.

One of the hazards of such early-stage drug trials is "selection bias." Doctors are supposed to choose patients who have a very poor prognosis, but they have a tendency to pick only the hardiest in that group. "We want them to be alive through the end of the trial," Dr. Eton says. As a result, early trials can make a treatment look more effective than it really is. To get marketing approval for a drug, researchers must conduct a more rigorous round of trials in which patients are randomly divided into a group that gets the experimental therapy and another that serves as a control group. That allows doctors to compare outcomes of equally ill patients.

In the melanoma trial that included Mr. Dillon, the first patients received their vaccines less than two years ago. Of the original 36, 19, or 53%, are cancer-free or have cancer that has stabilized. Those results have yet to be published or presented in a scientific forum, Dr. Eton says.

Of the 38 patients receiving custom-made vaccines in the Antigenics trial for kidney cancer, nine, or 24%, either have seen their tumors stop growing or are free of disease. The success rate is considered good for such severely diseased patients, Antigenics says.

Avax Technologies Inc., which is developing a custom vaccine for melanoma, found that, five years after having surgery to remove their tumors, 55% of patients who got its vaccine remained alive; without the therapy, less than half that number would have been expected to survive, it says. The Kansas City, Mo., company, which published its study in 1997 in the Journal of Clinical Oncology, now is conducting a larger, randomized trial to see if those results hold up.

For reasons researchers don't understand, the vaccines don't seem to help everyone. Angel Perez, 42, a Hollywood, Fla., physician diagnosed with metastatic kidney cancer in March, tried the Antigenics vaccine. But after nine shots, his cancer spread to his brain. Now, he is getting more vaccine in conjunction with a chemotherapy drug his doctors hope will boost his immune system. "I realize the chances are very small," Dr. Perez says. "I'm trying to buy some time."

Even if the vaccines prove effective, they also need to be practical. Hoping to show it can custom-make vaccines reliably and cost effectively, Antigenics has built a manufacturing facility outside Boston. There, two technicians working together grind tumors gently with a pestle and use a centrifuge to filter out contaminants.

After two years of work, the company has shaved production time to 10 hours and costs to about $3,000 a patient, says Antigenics Chief Executive Garo Armen. Even without further savings, the company could sell the final product for $10,000 to $15,000 and still have a healthy profit margin, he says.

There are other pitfalls to contend with, however. Bruce Wallace, a 59-year-old from Columbus, Ind., had kidney cancer that had spread to his lungs. "They told me I had 12 to 18 months," he says.

After Mr. Wallace enrolled in the trial at M.D. Anderson, doctors removed his kidney tumor and used it to make a vaccine. He received his first injection in May and got nine subsequent doses. By September, scans showed that several of the lung tumors were shrinking. But he was horrified to learn there was no vaccine left.

There was only one way to get more -- to try to make some from the small tumors in his lung. The surgery would leave him with an eight-inch scar, and there was no guarantee the tumors would provide enough material to make vaccine. A few weeks after the operation, Mr. Wallace learned that the lab had produced five more doses. It's not a lot, but, "I'm one happy camper," he says.

Dr. Armen, the CEO, says Antigenics is working on ways to get more vaccine out of each tumor so that supplies won't run out at critical junctures.

Some companies, however, have decided the personal approach just isn't worthwhile. Bristol-Myers Squibb Co. says it studied several cancer vaccines, including individualized ones, and finally decided to collaborate with Progenics Pharmaceuticals Inc., a Tarrytown, N.Y., company that has just begun testing an off-the-shelf vaccine for melanoma. "Customized products are going to be much more expensive," and there are "too many things that can go wrong," says Bruce J. Maddon, Progenics's CEO.

Others think the personalized vaccines may be a mere stepping stone. Genzyme Corp., of Cambridge, Mass., and Cell Genesys Inc., a Foster City, Calif., company it agreed to buy last month for $350 million, are both testing customized therapies. But Mark A. Goldberg, Genzyme's vice president of medical affairs, believes that, eventually, patients will be given a test that doctors will use to create the specific vaccine they need from a palette of mass-produced ingredients.

While Mr. Dillon is grateful for the hand-crafted version he received, he isn't taking its success for granted. On his way home to Ohio he stops off at M.D. Anderson's chapel. "I'm not going to stop praying," he says.

Health

AstraZeneca Researchers and Others
Progress on Hard-to-Treat Cancers

By ROBERT LANGRETH and MICHAEL WALDHOLZ
Staff Reporters of THE WALL STREET JOURNAL

Cancer researchers presented promising early test results of several drugs that exploit new insights into the biology of cancer cells to attack some of the hardest-to-treat cancers.

At a scientific meeting in Washington Tuesday, researchers presented early-stage human-trials results of a new gene-based cancer drug from AstraZeneca PLC of Britain.

The drug is one of several in development designed to block a protein called EGF receptor that is overabundant in many cancers of the lung, breast, head and neck, and prostate. The test results indicated the drug may stabilize difficult-to-control tumors, and, in some cases, shrink them significantly.

"We were able to show that a laboratory concept has relevance to the care of patients," said Mark Kris, a lung-cancer specialist at Memorial Sloan-Kettering Cancer Center in New York who helped conduct the trial.

The drug, brand-named Iressa, inhibits the activity of EGF receptor, a protein that sits on the surface of cancer cells and receives messages from growth hormones telling a cell to divide. In some cancers, the tumor cells overproduce copies of EGF receptor, which helps lead to the aberrant and relentless growth seen in cancer cells.

At the science meeting, researchers at Memorial Sloan-Kettering reported that, in a test of 64 patients with advanced stages of cancer, the drug was able to stabilize or reduce tumor size in 15 test subjects. In four patients with lung cancer, one of the most difficult of all cancers to treat, the drug caused major tumor shrinkage. All four patients are still responding to the drug after several months, the researchers said. This number of responses is considered significant, given the extremely low response rate to most treatments for advanced lung cancer.

Researchers at AstraZeneca hope the drug will have an even more powerful effect when combined with standard chemotherapy drugs or radiation. The researchers said Iressa doesn't appear to cause the kind of severe nausea and other toxic effects often produced by standard chemotherapy; its side effects are an acne-like facial rash and diarrhea.

George Blackledge, medical director of oncology for AstraZeneca, said that large-scale human tests will begin early next year.

AstraZeneca is competing with several other companies working on EGF receptor blockers, including Pfizer Inc. and ImClone Systems Inc., a small New York biotechnology company.

Last May, researchers at M.D. Anderson Cancer Center in Houston reported that an injectable protein against EGF receptor made by ImClone also produced an effect in difficult-to-treat head and neck cancers, when combined with a widely used chemotherapy drug. Imclone is now conducting a large trial of the drug, C225. Pfizer said Tuesday at an analyst meeting in New York that its experimental EGF receptor-blocking drug, CP358,774, was in the second stage of human testing for ovarian, lung and head and neck cancer.

At the science meeting in Washington Tuesday, the first of its type to be jointly sponsored by the American Association of Cancer Research, the U.S. National Cancer Institute and the European Organization for Research and Treatment of Cancer, researchers also presented promising reports on other cancer-attacking approaches. Several companies are targeting cancer-growth factors, such as tyrosine kinase.

Researchers from the Parker Hughes Cancer Center in St. Paul, Minn. reported results from a small, preliminary test showing that a experimental drug, B43Genistein, was active in treating patients with acute lymphoblastic leukemia, or ALL, that hadn't responded to standard cancer therapy. The researchers said their early study was the first to show that blocking so-called tyrosine kinase enzymes, which are part of the same cell-growth signaling pathway as EGF receptor, was useful in treating a leukemia cancer.

A separate report by researchers in Germany working with American Home Products Corp.'s Wyeth-Ayerst Research unit, showed that an experimental agent, CCI-779, was well-tolerated. Of 12 patients treated, the drug was able to reduce tumor size in three patients with kidney cancers that hadn't responded to previous therapy. The drug blocks the action of an enzyme mTOR, that regulates the synthesis of proteins that promote cell division, the researchers said.

Researchers from Symphar SA, a closely held Swiss drug maker, reported that its experimental drug Apomine appears to block tumor growth by inhibiting the action of still another newly found cell-growth protein called FXR. The company is co-developing the drug with publicly traded Ilex Oncology Inc., San Antonio.

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Avax Technologies Prepares to Sell Personalized Skin-Cancer Vaccines

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