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Doctors at Carolina have opened their first clinical trial of a vaccine treatment for advanced breast cancer.
After more than four years of test-tube and animal studies, researchers at
the Lineberger Comprehensive Cancer Center will find out if intravenous
infusions of their genetically engineered protein fragments will stimulate a
person's immune cells to recognize and kill breast cancer cells, causing
advanced breast tumors to shrink.
"This breast-cancer vaccine is not a shot -- it's a `vaccine' because it
should work by enhancing the patient's own immune response against their
tumor," said Lineberger member Jonathan Serody, associate professor of medicine
and microbiology and immunology in the School of Medicine.
"This is the first use of a vaccine directed against a modification of a
specific part of the HER-2/neu protein found on breast-cancer cells. People
have tried using engineered proteins in the treatment of melanoma, but not for
breast cancer."
A breast-cancer patient from Rochester, N.Y., was scheduled for her first
vaccine infusion July 6.
Serody said that current treatments, although helpful, do not cure an
adequate number of women with advanced breast cancer, in which the disease has
spread beyond the breast.
"Often women with this disease have responses to treatment, but these are
of brief duration and are not durable," he said.
At the heart of the new treatment is the dendritic cell, a type of white
blood cell that alerts the immune system to the presence of abnormal cellular
proteins. The dendritic cells snatch fragments of these proteins and race to
the lymph nodes to display them as targets for an immune response. Regiments of
killer T-cells then proliferate, seek out and cause the destruction of cells
carrying the targeted protein.
Led by Ed Collins, Jeffrey Frelinger, Roland Tisch and Serody, the Carolina
team found a way to engineer dendritic cells to target the protein HER2/Neu,
which is found in tumors of about one-third of women with breast cancer. To
make the vaccine, the team removes progenitor cells -- dendritic cell
precursors -- from the patient's blood.
"At any one time, the percentage of dendritic cells in the bloodstream is
quite small, maybe one-hundredth to one-thousandth of the cells in the
bloodstream," Serody said. "So we need to increase that number initially by
giving the person injections of growth factor, which increases the number of
immature progenitors in the blood. Then we expand those cells greatly in the
lab dish by adding other proteins that allow for dendritic cell growth."
An engineered protein fragment of HER2/Neu is coupled with dendritic cells
and re-infused into the patient. This molecular structure of the fragment has
been changed to boost the response of T lymphocytes to kill breast cancer
cells.
In the clinical trial, which is supported by the Breast Cancer Research
Foundation, patients will be randomized to receive either dendritic cells
coupled to the engineered HER2/Neu fragment or a fragment of the non-engineered
(normal) protein.
Dosages will vary, with patients receiving escalating doses of the
dendritic cells during the trial.
The treatment consists of three 30-minute infusions three weeks
apart.
"We anticipate two years to complete the trial based on enrolling 25
individuals," Serody said. "If you respond to the treatment, you may be
eligible to continue treatment for as long as you want. We're looking for
clinical regression of established tumors. By definition, this means at least a
25 percent shrinkage of established tumors."
Serody acknowledged that the engineered protein may prove no more effective
than treatment with the standard protein. This is the reason for evaluating
both treatments in the trial.
Why enroll in this clinical trial?
"In the setting of metastatic disease, even if the disease is stable, very
few are cured," Serody said. Less than two percent of women with advanced
breast disease survive 10 years after diagnosis, according to recent
data.
"We believe that the vaccine can be given safely," Serody said. "Our hope
is that by using very sophisticated techniques to monitor for an ongoing immune
response against the tumor, we can determine if the vaccine has a benefit in
the treatment of advanced breast cancer."
To qualify for the Carolina vaccine trial, women must meet the following
criteria:
* Their cancer has advanced beyond the breast to distant sites.
* Their disease is stable, defined by lack of progression measured
clinically or radiographically over a period of one month.
* The patient's cells must express the HLA (tissue type) A2 protein, which
is present in 30 to 40 percent of the population. Patients will not know their
tissue type and this will be evaluated prior to the collection of cells for
treatment.
Also, participants cannot receive chemotherapy while in the trial, although
previous treatment with chemotherapy is acceptable. Participants may receive
hormonal therapy during the trial.
According to Serody, this vaccine trial also marks a first for Lineberger:
the translation of basic research to treatment totally in-house -- that is,
going from test-tube to mice to humans without collaboration outside
Carolina.
"Our group made the altered compound, did all the pre-clinical work in
animals and are now taking this to people," Serody said. "This is how we
envision doing things in the next millennium."
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