Apr. 18, 2007 Mayo Clinic researchers have designed a new strategy in the promising field of cancer vaccine research that's proven to be successful in boosting T cells -- the immune builders akin to a super defense force against cancer cells. Scientists say their strategy may prove to be more successful than methods currently under study and in clinical trials.
Using vaccines to prevent or slow the growth of cancerous tumors is based on the premise that the body's immune system can be strengthened with an engineered vaccine that would stimulate an antibody and cellular response against cancer cells. Cancer vaccines are still considered experimental and so far, research results have been mixed. New studies, such as this, demonstrate that researchers are closing in on designing viable cancer vaccines, the investigators say.
In this study, Pilar Nava-Parada, M.D., Ph.D., and colleagues designed a synthetic peptide vaccine that stimulated an anti-tumor T cell response that recognized and successfully waged a battle against the spread of breast cancer cells in mouse models. (T cells are white blood cells with a key function in immune response.) Dr. Nava-Parada was a postdoctoral fellow in immunology at Mayo Clinic when she and Esteban Celis, M.D., Ph.D., began this research, which they planned to continue at Tulane University and Louisiana State University in New Orleans. But Hurricane Katrina struck before they had a chance to resume the research, so Dr. Nava-Parada returned to Mayo Clinic in Rochester where she began the research anew.
In female mouse models bred with the cancer-producing oncogene HER-2/neu, researchers administered a synthetic peptide vaccine during the early stage of tumor development. The experiment was effective in 100 percent of the study samples by either slowing or stopping the progression of breast cancer. In at least one case, the vaccine worked for as long as 39 weeks.
Because the use of synthetic peptides alone generally does not trigger a strong immune response, researchers administered the vaccine in combination with a Toll-like receptor stimulant that is designed to mimic the way in which an invading bacterial agent would induce an immune response in humans.
Under normal conditions, the response is generally strong enough for the body to recognize and attack invading bacteria. Researchers used this strategy, but also introduced anti-CD25 antibodies to increase the immune response. These antibodies control the production of T regulatory cells that can prevent the vaccine from doing its job, but by combining the two strategies (immunization and depletion of T regulatory mechanisms), the vaccine successfully passed through the T cell checkpoint. This approach was successful in stimulating an effective immune response.
"We found that we could train the immune system to recognize these synthetic peptides as dangerous foreign agents of the HER-2/neu gene by mimicking what the bacteria would do in your body. The body responded by killing everything that expressed HER-2/neu in high amounts," Dr. Nava-Parada said. In addition, "we estimate that in a real life scenario, we could probably use this technique to decrease the number of immunizations a patient would need (one instead of three), to build an immune response strong enough to destroy the tumor."
Dr. Nava-Parada said that up until now, researchers undertaking similar work have only been able to get vaccines to work in about 30 percent of HER-2/neu study models, but only by depleting T regulatory cells, which can have negative side effects, such as an autoimmune disorder. "In our study we showed that we can prevent tumors without depleting these cells and can achieve this success only by using a bacterial-like adjuvant administered with the right peptide," she said.
In addition, Dr. Nava-Parada said that other studies fail to accurately represent human cancers because they measure acute rejection of a tumor cell line that is produced in the laboratory and then injected into healthy animal models. Study models like the one described in this AACR presentation are thought to be more realistic because the study considers the entire natural history of the tumor in an animal that harbors the HER-2/neu gene.
"When the animal has a precancerous lesion, we vaccinate it and closely follow the appearance of the spontaneous tumor through its life. Conducting the research in this manner allows us to gain a clearer insight into a real-life cancer patient's situation," she said.
Cancer vaccines are intended for patients with a strong genetic predisposition or personal history of cancer; patients who do not respond to traditional therapies; or, as a preventive measure for patients who have successfully completed traditional courses of treatment, such as surgery, radiation and/or chemotherapy.
Cancer Vaccine Mouse Models and Research Data Lost in Hurricane Katrina
Dr. Nava-Parada was a post-doctoral fellow at Mayo Clinic where she worked in the laboratory of Esteban Celis, M.D., Ph.D., a specialist in immunology and cancer research pursuing the development of a vaccine to treat and prevent breast cancer. In November 2004, Drs. Celis and Nava-Parada moved the research from Minnesota to Louisiana where they planned to continue the work with Tulane University and Louisiana State University. But Hurricane Katrina struck before they could resume the research. The data and colony of mice developed for the study were destroyed.
"When I lost the work, I decided to return to Mayo where Dr. Larry Pease, Ph.D., (chief of immunology) graciously gave me space in his lab to continue this work," Dr. Nava-Parada said.
Rebuilding the colony of mice is a slow and tedious process, but the research team successfully re-established the colony in approximately 16 weeks.
The study's principal investigator is Esteban Celis, M.D., Ph.D., a specialist in immunology and cancer research, formerly of Mayo Clinic, but currently with H. Lee Moffitt Cancer Center & Research Institute in Florida. Other authors include: Larry Pease, Ph.D., and Keith Knutson, Ph.D., both of Mayo Clinic; and, Guido Forni of the University of Torino in Italy.
The research was supported with grants from the National Institutes of Health (Esteban Celis, M.D., Ph.D.), AACR (Pilar Nava-Parada, M.D., Ph.D.) and Mayo Clinic.
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