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Friday, March 14, 2008
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 38 days.
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 to http://ccr.cancer.gov/staff/staff.asp?profileid=5776.
For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
About the National Institutes of Health (NIH): 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. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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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.