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. Talmadges 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. 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.
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 cant 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.
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.
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.