Experimental Patient-Specific Cancer Vaccines Show Promise

By Ronald Rosenberg, The Boston Globe

For all the cancer recoveries that Dr. Robert Amato has seen, few have surprised and impressed him more than that of a 50-year-old man who was successfully treated for kidney cancer, only to see tumors spread to his lungs.

Amato, an oncologist and clinical investigator at the University of Texas's MD Anderson Cancer Center in Houston, gave the man eight weekly injections of an experimental cancer vaccine that was made, in part, from the patient's own cancer cells by Antigenics LLC, a 5-year-old biotechnology company in Framingham, Mass.

Soon after the last injection, the tumors in his lungs began to disappear, leaving just scars, which surgery subsequently removed. Today, 17 months after his first inoculation, the man is still cancer-free.

``He was one of our first patients tested . . . and his tumors were gone,'' Amato told Antigenics officials, cancer researchers, and investment bankers last month at the opening of the privately held company's new $5.5 million biomanufacturing and research facility in Woburn, Mass.

Amato's patient was among 38 who suffered a kidney cancer relapse and participated in Antigenics' phase 1 safety trial to test its custom-made vaccines using three different doses. Five patients have remained cancer-free and four have experienced partial recoveries, prompting the company to progress to a phase 2 trial that will use a single dose of the vaccines to more carefully measure recoveries.

The nine patients are part of a recent wave of promising clinical results for treating certain cancers using experimental -- and controversial -- therapeutic vaccines derived, in part, from the patients' own cancerous tumors. Still in their infancy, these promising vaccines attack the abnormal proteins in cancer cells. And while these vaccines are still a tiny fraction of the $7.5 billion spent annually on cancer medications, some specialists see them as potentially plausible alternatives to today's cancer drugs, many of which have significant side effects.

Other medical researchers see promise in the vaccines because, they say, cancerous tumors and melanomas are individually distinct, like a fingerprint, making them difficult to identify and treat with one single off-the-shelf drug.

``The jury is still out on patient-specific vaccines, because cancer is not one disease but many, and there is evidence of some promising results today that we did not see a decade ago,'' said Dr. Stanley Nathenson, professor of microbiology and immunology at New York's Albert Einstein School of Medicine.

Still, none of the proposed vaccines is considered a possible cure. Instead, they are expected to help patients who have already undergone such standard anticancer procedures as surgery, radiation, and chemotherapy, but have suffered a relapse. They need a treatment that has fewer side effects, yet is more effective in fighting cancer in older patients with weakened immune system.

Since early clinical testing of patient-specific vaccines began two years ago, none has been approved by the US Food and Drug Administration. Several vaccine developers are hoping to launch major testing with hundreds of patients next year, with an eye toward gaining FDA marketing clearance in 2002.

Even then, it will take about five years to assess the status of patients' recovery to sort out whether the new type of cancer treatment is a long-term solution. Unlike preventive vaccines that ward off polio or measles, that stimulate the immune system to protect against invading infectious, therapeutic cancer vaccines go to work immediately battling diseased tumors and melanomas.

But despite their promising outlook, they are seen as merely a temporary step on the road toward developing off-the-shelf vaccines that will cost less and be available to treat a wider group of cancer patients.

``The concept of these patient-specific vaccines goes back more than 60 years,'' said Dennis Panicali, president of Therion Biologics Inc., a Cambridge, Mass. company working with the National Cancer Institute to develop seven therapeutic cancer vaccines that are not patient-specific. ``And while the scientific and physician community has taken notice, they are always saying, `If we can only make it little bit better.' ''

Genzyme, Antigenics, and several other companies think they have made major strides with a new generation of vaccines. Antigenics, which reported an 80 percent cure rate in mice, is one of several companies developing patient-specific cancer vaccines that boost the body's anticancer immune response.

Unlike many other proposed therapeutic cancer vaccines, which are made in laboratories, a patient-specific vaccine requires first harvesting a tumor biopsy, which is then packed in ice and shipped overnight to a processing lab. Depending on the technology, the lab creates the vaccine and sends it to the patient's physician, who over the course of three to eight weeks, injects it into the patient's skin.

These drugs are sometimes referred to as autologous vaccines, because they combine a patient's own cancer cells with a type of bacterium or other agent that provokes a major immune response.

``We believe that our individualized cancer vaccines can be used to treat pancreatic, kidney, and skin cancers,'' said Garo Armen, a cofounder and president of Antigenics, which developed the personalized cancer vaccines that Amato used in Houston. He said the company's new Woburn facility can produce 7,000 individualized vaccines per year, at a cost to the patient of $15,000 per treatment.

Antigenics has found a way to attack tumors using a class of proteins called heat-shock proteins, which when extracted from the patient's own tumors and purified, can be used to stimulate the immune system to attack cancer cells.

Based on nearly 20 years of research by Pramod Srivastava, a cofounder of Antigenics and a cancer specialist at the University of Connecticut School of Medicine in Farmington, a patient's heat-shock proteins are extracted from the tumor, processed, and sent back in the form of a vaccine.

Armen, who hopes to gain FDA approval in three years, said the cost is comparable to standard chemotherapy, but still higher than some newer cancer-fighting drugs such as Genentech Corp.'s breast cancer drug Herceptin.

Recently, Genzyme Molecular Oncology, a unit of Genzyme Corp. of Cambridge, Mass., said it has tested two melanoma vaccines in a phase 1 product safety trial in more than 50 patients, with 20 percent having ``dramatic clinical responses.''

In March, the company launched a phase 2 clinical trial of 24 patients who have the most severe form of skin cancer, led by Dr. Frank G. Haluska of the Massachusetts General Hospital Cancer Center. Patients will receive six injections over three months, with the first results due next year.

At Dana-Farber Cancer Institute, several clinical studies are underway to test cancer vaccines from Cell Genesys Inc. of Foster City, Calif.

``The Boston area was the only place where we could get the technical expertise, the biotechnology researchers, and a major facility for our needs,'' said Armen, who shuttles between Antigenics' Manhattan headquarters and the facilities in Woburn and Framingham.

Several other personalized vaccines are being tested around the country to treat lung, ovarian, colon, and prostate cancers. Dendreon Corp. this fall expects to launch a pivotal clinical trial to test its dendritic cell therapy on men with late-stage prostate cancer.

The Seattle company harvests a patient's white blood cells and separates out a component called dendritic cells, which are produced by bone marrow to circulate throughout the body. Considered the most powerful stimulator of immune responses in the body, the patient's dendritic cells are cultured for two days with specific cancer markers, or antigens, that are absorbed into the cells to produce a targeted response against prostate cancer.

In the company's longest study, 20 prostate cancer patients were tested and nearly half have not suffered a relapse in nearly a year, according to David Urdal, Dendreon's chief scientific officer.

And Avax Technologies of Kansas City recently launched a pivotal clinical trial for 400 patients with melanoma who have experienced a relapse since their cancers were removed surgically. Melanoma is the most serious form of skin cancer.

In April, the company reported that earlier testing of 40 patients showed 17 still alive, of which 12 remain cancer free. Avax is projecting its patient-specific vaccine would cost about $20,000 per patient if it gains FDA approval, according to Ernest W. Yankee, Avax executive vice president. ``Right now, the large pharmaceutical companies are not sure that this kind of vaccine technology is really practical,'' said Yankee.

Indeed, major drug companies would rather deliver off-the-pharmacy-shelf products that they can sell in large quantities to hospitals and health maintenance organizations. Making small quantities of custom vaccines quickly and shipping them across the country overnight raises concerns with the FDA over the quality of each vaccine batch and whether it is consistent for each patient, said Denis R. Burger, president of AVI Biopharma Inc. of Portland, Ore., which is developing a laboratory-produced therapeutic vaccine for colorectal cancer.

``We know our cost of goods is $100, which means we can charge under $1,000, so once we get real conventional therapeutic vaccines approved, autologous vaccines are out the window,'' said Burger.

Nonpatient-specific vaccines like those made by Therion Biologics and AVI Biopharma are attracting pharmaceutical company interest.

Last fall, SmithKline Beecham PLC, one of the largest vaccine makers in the world, expanded its strategic partnership with Corixa Corp. of Seattle, a 5-year-old developer of vaccines for cancer and tuberculosis, to include therapeutic vaccines for ovarian and colon cancers.

But some oncologists, such as Nathenson at Einstein, say that any drug that is effective and less toxic than some current medications is worthwhile.

``If these patient-specific vaccines are approved, they will meet an unmet medical need of prolonging survival with a better quality of life,'' said Dr. Mark A. Goldberg, an associate professor at the Harvard Medical School and vice president of medical affairs at Genzyme Molecular Oncology. ``But the long-term goal is to develop off-the-shelf vaccines.''