November 2001

From University of Nebraska Medical Center

Genetic vaccine for metastatic breast cancer shows promise in mice studies

Scientists at the University of Nebraska Medical Center have developed a genetic vaccine for metastatic breast cancer and other tumors, which shows great promise in early studies in mice. The findings are reported in the Nov. 15 issue of Cancer Research, a leading cancer research journal.

The vaccine uses a combination of components that are being used in existing clinical trials for other diseases. The approach they developed combines DNA and adenovirus gene delivery mechanisms. Adenovirus is a common virus naturally found in the lungs. Together, the combination can deliver the p53 gene as a vaccine for breast cancer. P53 is a tumor suppressor factor that changes in 50 percent of all cancers, including lymphoma, leukemia, breast, lung, colon and prostate cancer.

"This is a unique genetic vaccine," said James Talmadge, Ph.D., professor of Pathology and Microbiology at UNMC and principal investigator on the study. "The results we saw in our mice studies were quite dramatic and provide encouragement that we are potentially on to something that could have significant implications in humans."

Dr. Talmadge is director of the Laboratory of Transplantation Immunology at UNMC. First author of the study was Prahlad Parajuli, Ph.D., a post-doctoral fellow in Dr. Talmadge's lab who now works at the Karmanos Cancer Institute, Wayne State University, Detroit.

The study involved multiple groups of mice all with metastatic breast cancer. Metastasis is the process by which cancer spreads beyond the organ in which it originated. One group received no vaccine. The second and third groups received individual components of the vaccine and the fourth group received both vaccine components.

The non-vaccinated mice all died within 30 days. Mice receiving individual components of the vaccine lived for up to 60 days, while mice receiving both components of the vaccine were cured 40 percent of the time.

"The work by Dr. Talmadge is very promising," said Kenneth Cowan, M.D., Ph.D., director of the UNMC Eppley Cancer Center. "The development of a vaccine to prevent breast cancer recurrences would represent an important addition to clinical therapy for breast cancer, a disease that will affect more than 180,000 women in the U.S. this year. Since p53 is commonly altered in many other cancers, this vaccine could have very far reaching implications for cancer prevention." According to the National Cancer Institute, 1 in 8 women in the United States (approximately 12.8 percent) will develop breast cancer during their lifetime. For those who develop metastatic breast cancer, only 35 percent will survive two years or more.

Tumor associated antigens, such as p53, are molecules found on the surface of tumor cells. They can stimulate a unique subset of white blood cells to respond to and kill tumor cells.

"Using the combination of DNA and adenovirus is critical," Dr. Talmadge said. "The adenovirus can stimulate a host response to itself and can deliver a large amount of the p53 gene, but it can't be used to boost the immune response. In contrast, while the DNA portion of the vaccine does not induce a strong immune response, it can boost the immune response initiated by the adenovirus delivered vaccine."

Dr. Talmadge said the adenovirus used in these studies is "safe," as it is unable to reproduce in humans or mice. The adenovirus is produced by Canji, a biotech company in San Diego, which is affiliated with Schering-Plough Corporation.

The breast cancer vaccine also used a growth factor, Flt3L ligand, to induce a strong immune response, he said. This growth factor is being studied clinically by Immunex Corporation, a biopharmaceutical company in Seattle. The additional benefit of Flt3L administration in this study is consistent with the potency of this cytokine as an immunological adjuvant.

"While additional work is needed to further improve this therapeutic approach in both the preclinical and clinical settings, the overall approach of using genetic vaccines is quite promising," Dr. Talmadge said. "By taking advantage of the unique attributes of each delivery system, in combination with growth factors, it appears to improve the immune response to a tumor antigen and ultimately extend survival.

"The availability of the individual vaccine components suggests that there is the potential for a rapid translation to clinical studies." Dr. Talmadge said he hopes clinical trials in humans can begin within the next year.












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