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CANCER: TURNING THE
CORNER
Going after cancer's Achilles'
heel
By Richard Saltus,
Globe Staff, 08/03/98
They were hailed as biological ''guided
missiles'' when they were developed in the 1970s, but
monoclonal antibodies fell short of their targets in early
tests against cancer and other illnesses.
In a remarkable turnaround, however, these biotech
weapons are now leading the charge in the early testing of
new, highly specific drugs that aim for the genetic
Achilles' heels of cancer cells.
Already, one monoclonal antibody drug has been approved
to treat an immune cancer, lymphoma, with fewer side effects
than standard chemo agents. Another, Herceptin, is on a Food
and Drug Administration ''fast track'' toward approval after
showing encouraging results against metastatic breast cancer
in cases where other therapies had failed.
Dr. Dennis Slamon, a University of California at Los
Angeles scientist whose research led to the development of
Herceptin, was in the spotlight at a major cancer meeting
this spring.
''This is the first time when molecular biology has
really paid off,'' he declared, ''where we've identified a
genetic alteration, showed its role in a disease process,
and then targeted it.''
Herceptin is a monoclonal antibody that recognizes and
binds to a molecule found on the surface of about 30 percent
of breast cancer cells. The molecule, known as the HER-2/neu
receptor, acts as an on-off switch. When on, it makes breast
cancer especially aggressive and fast-moving. Herceptin
keeps the switch turned off.
Because the HER-2/neu protein isn't present on normal
breast cells, Herceptin selectively attacks the cancer.
Results announced in May showed that the drug, combined with
the best standard chemotherapy agent, caused tumors to
shrink by half or more in 49 percent of women, compared with
32 percent of those on the chemo alone.
A year later, 28 percent of women on Herceptin had no
evidence of tumor progression, compared with 14 percent in
the chemo-only group.
Because they're expensive and must be given by injection,
monoclonals may not be the ultimate cancer drugs, but
they're further along in development than most of the
''small molecule'' drugs that eventually may be more
selective and easier to administer.
Antibodies are the proteins made by the body's immune
system cells to recognize and attack specific foreign
invaders, such as infectious germs. The body makes millions
of antibodies, each of which has a specific shape to
recognize and bind to a foreign molecule.
Twenty years ago, scientists discovered how to make large
quantities of identical antibodies - hence ''monoclonal'' -
in mice. There were high hopes that these would be ''magic
bullets'' that could be tailored to identify and latch onto
unique structures on cancer cells. The antibodies could then
be loaded with toxins or radioactive substances that would
destroy the cells.
Antibodies can be used against cancer in three ways, says
Dr. Mark Kaminski, a researcher at the University of
Michigan School of Medicine:
They can bind to cancer cells and alert the immune system
to attack them.
They can latch onto cells and trigger a signal within
each one that halts its growth or causes it to commit
suicide. Or they can block growth signals from outside the
cell and squelch growth that way.
They can serve as guided missiles, homing in on cancer
cells after scientists attach a molecular warhead, in the
form of toxins or drugs, that kills targeted cells.
Disappointing start>
for antibody approach
In spite of all that, antibody treatments were deeply
disappointing for the first 10 years or so.
''They were the hot technology in the late '80s,'' says
Donald Drakeman, president of Medarex, Inc., in New Jersey.
''It was an exciting opportunity, and like with all
brand-new technologies, no one figured out the problems. By
the early '90s antibodies became almost a dirty word.'"
The main problem was that patients' immune systems
recognized the proteins from the mice used to make the
monoclonals as foreign and attacked them. The drugs were
destroyed before they could reach their targets.
As researchers learned to ''humanize'' the antibodies by
replacing most of the mouse components with human ones,
their effectiveness rose.
Over the last 10 years we learned more about how to use
them and which [molecules] are especially good
targets,'' says Drakeman.
And now the new drug Herceptin, made by Genentech, Inc.,
of South San Francisco, has put monoclonal antibodies back
in the spotlight with its ability to fight breast cancer.
Genentech says it expects FDA approval by the fall and it
will be able to supply what is expected to be a large
market. (Some clinical trials of Herceptin are still open
for women who meet the criteria.)
Edith Sooy is a Massachusetts woman who took Herceptin in
the company's earlier trials and believes she is alive today
because of it.
Sooy, 54, of Dover, was treated for breast cancer in
1987, but discovered in 1992 that it had spread to her
lungs. The most potent standard drugs, like adriamycin and
the relatively new agent, Taxol, failed to help. ''They're
dreadful drugs'' because of their side effects, she says,
''and when they don't do anything for you, it's
depressing.''
Because her tumor was among the 30 percent that carry the
HER-2/neu genes, Sooy was able to enroll in a Herceptin
study at Boston University Medical Center. In early 1996 she
began taking the intravenous agent. Within a few months, her
tumors had shrunk by 50 percent of more, and the toxicity
was very mild. ''It's heaven - if it keeps your cancer in
check,'' she says.
Unfortunately, the tumors grew back. Since then, she has
been on a series of combinations of chemo drugs and
Herceptin. Her disease has progressed, but slowly. ''I think
I'm very lucky to be alive and well and doing my gardening.
I have to think it has to be due in part to the Herceptin,''
she says.
Other monoclonal antibodies have shown effectiveness
against non-Hodgkin's lymphoma, an immune-system cancer. In
addition to the already approved Rituxan, an experimental
monoclonal antibody called Bexxar is undergoing testing at
the University of Michigan, where Kaminski has reported a
series of promising test results. All of the newly diagnosed
patients with advanced low-grade non-Hodgkin's lymphoma have
responded to the drug, and 17 of 24 patients followed for at
least six months have had a complete remission, Kaminski
reported.
A trial is now in progress to see whether patients who
relapsed after the first round of treatment will respond to
a second dose of Bexxar. Thus far, says Kaminski, ''we've
gotten the majority of patients back into remission.''
That's a huge selling point for patients who have
volunteered for trials. ''What you go through in this
treatment is so much less [traumatic] than
chemotherapy, so if you had to do it again, it wouldn't take
as much out of you,'' says Teresa Singh, 39, who chose
treatment with Bexxar after being diagnosed in 1996 with
lymphoma
She was told that with conventional chemotherapy she
might be put into remission - free of disease as far as
standard tests show - but that she would likely relapse. One
expert told her she might live 6 to 9 years after diagnosis;
another put it at 10 to 15 years.
''I have [plans for] a lot longer
than that to live,'' she says.
Bexxar seeks out a target protein, called cd20, on the
surface of the affected blood cells. To the antibody is
attached radioactive iodine, which at close range can kill
those cells
Singh received the treatment in a special hospital room
in which she was shielded by lead slabs and had to take
precautions to avoid contaminating others. ''I had to flush
the toilet three times'' to ensure that contaminated urine
was completely disposed of, she said.
Singh and other patients have been astonished to find
their swollen lymph glands and other sites of cancer shrink
quickly - sometimes within a week or two - after the
radioactive assault.
''I think oncologists don't raise their hopes too
easily,'' says Singh, ''and Dr. Kaminski is still very
conservative in the way he talks about this. I can't say I
never worry about it coming back, but I'm thankful I have
this treatment that isn't grueling... and there is hope for
a cure.''
This story ran on page C01 of the Boston
Globe on 08/03/98.
© Copyright
1998 Globe Newspaper Company
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