AUGUST 18, 2003

THE BIOTECH BEAT
By Amy Tsao and John Carey

On the Twisting Trail of Cancer Vaccines

While success has eluded huge drug companies and small biotechs so
far, scientists now have a better idea of what might work


As cancer researcher Dr. Olivera Finn tells it, therapeutic cancer
vaccines have a way of confounding scientists. "Once in a while,
there's a response. Once in a while, we see stabilization. Once in a
while, a patient lives longer than expected." After nearly 20 years
of studying vaccines, Finn says her work is still about "doing
everything you can imagine to eek out a little bit of success. That
won't solve the cancer problem.

Chief of immunology at the University of Pittsburgh School of
Medicine and author of a recent review of cancer-vaccine research in
Nature, still believes that cancer vaccines will become a reality.
And she's not alone. Vaccines remain one of the most promising -- and
daunting -- areas of cancer research. Even with all the advancements
in other cancer treatments in recent years -- like Genentech's (DNA )
and Idec's (IDPH ) respective antibodies Herceptin and Rituxan and
Novartis' targeted therapy Gleevec -- vaccines intrigue researchers.

In theory, they should cause fewer side effects than traditional
cancer drugs. The concept behind cancer vaccines differs from both
traditional vaccines and cancer treatments. The goal of a cancer
vaccine, unlike prophylactic shots for ailments like flu, isn't to
prevent disease but to trick the immune system, which has already
missed the existing cancer cells, to attack them. Unlike traditional
chemotherapy drugs, which kill cells unselectively, vaccines aim to
help the body kill off cancer cells only.

INCONCLUSIVE RESULTS. Some 13% of all new cancer treatments in
development are therapeutic vaccines, according to pharmaceutical-
industry consulting firm Decision Resources. Many heavyweights like
Genzyme (GENZ ) (through its Genzyme Molecular Oncology unit),
Aventis Pasteur (AVE ), and GlaxoSmithKline (GSK ) have ongoing
cancer-vaccine projects in early phases. The National Institutes of
Health is funding several projects. And a dozen or more biotechs have
vaccines at various stages of development, including Cell Genesys
(CEGE ), Genitope, and Therion Biologics.

At least eight vaccines are now in late Phase 3 testing. But so far
results from large trials have been discouraging. Two years ago,
Corixa's Melacine vaccine didn't produce the harsh side effects of
chemotherapy, but results were inconclusive, except in a subgroup of
patients. This summer, Biomira's (BIOM ) breast-cancer vaccine
Theratope, which is being developed with Germany's Merck, had a
similar result.

Finn thinks the trials have been flawed. While informative, none to
date, including trials she has been involved in, have merited the
broad human testing that has been done, Finn contends. Smaller
companies, often with modestly positive data at best, are often under
pressure to initiate big trials to keep their investors interested.
All of the failed studies then "look like a failure of our science,"
Finn says.

DUAL PATHS. The best prospects among therapeutic cancer vaccines may
ultimately be in earlier-stage research efforts -- projects that
began as knowledge of how to construct viable vaccines and became
more comprehensive. Vaccines like Melacine represent the best of an
early generation of such therapies, says David Fanning, Corixia's
chief operating officer, because they have "greater specificity and
cleaner ability to test for immune response."

Cancer-vaccine research falls mainly in two camps: antigen-specific
and whole-cell. The first approach tries to increase recognition of
antigens -- foreign substances that appear on intruding cells --
known to be related to certain cancers. Whole-cell vaccines are
tailored to a patient's own tumor cells or a combination of other
people's cancer cells. Test details vary -- in terms of the type of
patients selected, how the vaccine is delivered (with a virus or a
different method), what so-called adjuvant drug is used to prime the
immune system to best respond to the vaccines and which specific
antigens to go after.

Though many companies are still testing them, whole-cell strategies
are beginning to lose some luster while vaccines that target specific
antigens seem to be garnering more champions. With whole-cell
vaccines, it isn't clear which elements are having an effect on the
cancer. "We have so much knowledge in precision molecules and
understanding specificity, then we ignore it to get any kind of
immune response," says Finn.

Mitchell Gold, chief executive of Dendreon agrees: "With [whole-cell]
vaccines, it's a potpourri." At least two of the vaccines in late-
stage testing are whole-cell: Cancervax's Canvaxin and Antigenics'
Oncophage

RECOGNITION BOOSTER. An antigen-specific treatment with a shot at
approval is Seattle-based Dendreon's Provenge, which targets a
prostate-cancer antigen seen in 95% of men with that illness.
Provenge also has the added ingredient of a sample of a patient's so-
called dendritic cells, which boost the vaccine by alerting other
immune system cells to recognize antigens and mount an immune response

Provenge is now in its second Phase 3 trial. In 2001, Dendreon
reported, as had others before it, successful results in just a
subset of patients. Fortunately, the subset represented some 75% of
men with prostate cancer -- those with less aggressive tumors who
were no longer responding to hormone treatments.

Patients given Provenge saw their chances of surviving more than
double and experienced a significant delay in disease-related pain,
says Dendreon's Gold. "Others are promising, but I think the proof is
in our data," he says. All the data from the second Phase 3 trial
will be available sometime in 2005.

"THAT'S A CLUE." Earlier-stage anitgen-specific projects at French
drugmaker Aventis Pasteur are showing some promise. Dr. Neil
Berinstein, assistant vice-president for clinical oncology and cancer
program director, says the company has done four Phase 1 trials in
colorectal-cancer patients. "We're eager to move as fast as possible
on cancer vaccines," he says.

Aventis is using the CEA antigen, commonly seen in colon-cancer
cells, in a gene-therapy treatment. In response to the vaccine, the
body is supposed to make the antigen, which is then supposed to
stimulate the immune system to attack the antigen. "We've shown it's
safe and that most patients have a CTL -- i.e. cyotoxic lymphocycte,
or killer T-cell -- response to CEA," says Berinstein. "And in some
patients who failed chemo, we've seen a stabilization. That's a clue
that something is happening."

Berinstein, naturally, is bullish on the approach. "This will bea big
growth area," he predicts. "Sometime in the next decade, almost every
patient will receive a cancer vaccine." Not as the only therapy, he
hastens to add, but as part of a combination regimen. Aventis-Pasteur
is also doing trials in melanoma patients. "We've found that the
vaccine is safe, and we get high levels of T-cell activation -- and
some actual tumor response."

NO ANIMAL TESTING. While cancer vaccines continue to intrigue many
reasearchers, some companies are losing patience. Jean Stephenne,
president of GlaxoSmithKline's vaccine unit, said recently: "We have
reduced our effort in cancer vaccines. It's really a gamble." He says
one key problem is that no animal models exist, so the only way of
getting data is with human trials. Still, Glaxo is working with
Corixa on development of vaccines for breast and prostate cancer.
Trial data will be available in 2006, says Stephenne.

In the next two years, several companies will unveil results from
late-stage trials for cancer vaccines, but if the Phase 3
disappointments of the past are any indication, a real product on the
market could still be very far away. Nothing is for sure in drug
research, and the field will likely test the patience of investors,
the medical community, and cancer sufferers alike for many more years
to come.


Tsao covers biotech for BusinessWeek Online in New York and Carey
covers science and medicine for BusinessWeek in Washington
Edited by Douglas Harbrecht