|Modified Virus Vaccine Shows Promise in Mouse
Model of Breast Cancer
Researchers have shown that vaccinating mice with a modified form
of a virus containing proteins from breast cancer cells can kill
large breast cancer tumors and tumors that have spread to the lungs.
The rodent model of cancer used in this study closely resembles
a type of breast cancer seen in humans called HER2-positive. Although
other cancer vaccines have shown activity in the treatment of very
small tumors, their ability to influence large, established tumors,
such as many HER2-positive breast cancers, has proven difficult.
The study, led by researchers at the National Cancer Institute
(NCI), part of the National Institutes of Health, appeared in the
March 15, 2008, issue of Cancer Research.
Therapeutic cancer vaccines are intended to disrupt new or existing
cancerous growth by stimulating the body's immune system so that
it recognizes the cancer as an invader. These vaccines use certain
protein molecules on the surface of cancer cells, such as the HER2
receptor protein, as the triggers to initiate an immune response.
The modified virus used as a vaccine in this study showed activity
against ErbB2-positive tumors. The ErbB2 gene is known as HER2 in
humans, and neu is its counterpart in mice. Approximately
20 percent to 25 percent of breast cancers in women are HER2-positive
and tumors overexpressing the HER2 receptor protein are more aggressive
and more likely to recur than tumors that do not overexpress the
protein. Thus, the HER2 receptor protein is an important target.
"A therapeutic vaccine may offer an advantage over treatments,
such as monoclonal antibodies, that target a single site on a cancer
cell because it may induce the production of several different
antibodies that can target multiple regions on a receptor, making
it harder for the tumor to mutate and escape the effects of therapy," said
Jay A. Berzofsky, M.D., Ph.D., of the Vaccine Branch at NCI's Center
for Cancer Research (CCR).
The research team, led by Berzofsky, along with Jong Myun Park,
Ph.D., and Masaki Terabe, Ph.D., of the Vaccine Branch, and John
Morris, M.D., of the Metabolism Branch of the CCR, conducted a
series of experiments studying the effectiveness of a vaccine containing
a modified form of adenovirus, a type of virus that primarily affects
the respiratory tract, that expresses portions of neu (Ad-neuECTM)
in the treatment of breast cancer in mice. They also investigated
the possible mechanism by which the vaccine induces the destruction
of tumor cells.
To create their breast cancer model, the team induced tumors by
injecting TUBO cells — a mouse mammary cancer cell line that
highly expresses the neu receptor on its surface — under
the skin in mice. The research team found that when the Ad-neuECTM
vaccine and TUBO cells were injected at the same time, tumors did
not develop. In another experiment, the vaccine was administered
seven, 10, or 15 days after TUBO cells had been injected into mice,
and tumors had formed. The researchers observed that the tumors
were smaller seven days after vaccination; all the tumors had disappeared
between 25 and 45 days after the mice were vaccinated. The mice
remained tumor-free through the end of the study.
The researchers also looked at the effects of the vaccine on tumors
of different sizes. They found that although tumors as large as
2 cubic centimeters continued to grow for seven days after immunization,
these tumors did begin to regress by 10 days and disappeared about
30 days after a single vaccination. In a separate experiment, the
researchers observed that tumors as large as 3.5 cubic centimeters
disappeared after a single dose of Ad-neuECTM. Vaccination,
however, was not sufficient to treat tumors larger than 5.5 cubic
centimeters. Although these tumors did shrink, they started to
regrow two weeks after a single vaccination.
Metastatic tumors are more difficult to treat than original tumors,
so Berzofsky's team also investigated the efficacy of the Ad-neuECTM
vaccine on cancer cells (TUBO) that had traveled from the site
of injection to the lungs of the mice. They found that the timing
of vaccine administration and the number of metastatic tumors in
the lungs played a role in the effectiveness of the vaccine. Mice
given the vaccine on the same day as the TUBO cells were injected
did not develop metastases to the lungs. However, when the vaccine
was administered six days after TUBO cells, metastatic tumors did
form in the lungs and took more than two weeks to regress. In mice
with 25 metastatic tumors in their lungs, the tumors disappeared
in about 21 days with a single dose of the vaccine, and mice with
over 200 metastatic tumors in their lungs became tumor-free within
Conventional chemotherapy is often immediately active against
tumors, while therapeutic vaccines take time to act. Tumors tend
to grow for a while before regressing because of the time required
for the vaccine to induce an immune response. Once the immune response
was triggered, the tumors in this study were controlled and eradicated
within four to five weeks.
The researchers found that in vaccinated mice, the total ErbB2/neu protein
receptor levels decreased by 45 percent.
It remains to be demonstrated the exact cause of how the TUBO
cell is inhibited in this mouse model resembling HER2+ breast cancer.
More studies in animal models should help clarify the underlying
mechanism of this growth inhibition.
"These results show the potential for a vaccine that induces
antibodies to an overexpressed cell surface receptor such as HER2," said
Berzofsky. This study was done in mice and could progress one day
to testing in humans.
For more information on research in Berzofsky's lab, please go
For more information about cancer, please visit the NCI Web site
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
Park JM, Terabe M, Steel JC, Forni G, Sakai Y, Morris JC, and Berzofsky
JA. Therapy of Advanced Established Murine Breast Cancer with a Recombinant
Adenoviral ErbB-2/neu Vaccine. Cancer Research Vol.
68 No. 6. March 15, 2008.