) In this proposal we wish to explore the potential of Listeria monocytogenes, as a cancer therapeutic for NER-2/neu expressing breast tumors. We have shown using other tumor associated antigens that a recombinant L. monocytogenes that secretes a tumor specific antigen can not only protect against tumor challenge but cal also induce a regression of macroscopic established tumors after transplantation into normal syngeneic mice. This impressive anti-tumor response is probably due to the unusual ability of this facultative intracellular bacterium to escape the phagolysosome and live and grow in the cytoplasm cells. Antigens secreted by L monocytogenes, therefore, are very effectively targeted to both the class II and class I restricted pathways for antigen presentation resulting in strong cell mediated immunity. Thus this bacterium may be the ideal vaccine vector for boosting the TH1, CD4+ and CD8+ T cell response to tumor specific antigens as a cancer therapeutic. In order to determine how to optimize the use of L monocytogenes as a cancer vaccine in humans we will use the HER-2/neu transgenic mouse model of breast cancer to design and test the ability of L monocytogenes as a delivery system of HER-2/neu to overcome tolerance to spontaneously arising tumors.
In specific aim 1 we will construct strains of L monocytogenes that deliver Her-2/neu to the immune system as secreted polypeptide products and as a DNA vaccine. The goal of specific aim 2 is to test the ability of the Lm-Her-2/neu recombinants to induce the regression of established tumors in a transplantable HER-2/neu expressing tumor model developed by Dr Elizabeth Jaffee in Her-2/neu transgenic mice where HER-2/neu is a self antigen. Effective vaccines in this less stringent model will then be tested both their ability to impact on naturally arising tumors in the HER-2/neu transgenic mouse. Finally, in specific aim 2, we will compare the efficacy of the Listeria vector approach with a wider range of therapeutic approaches developed in the other laboratories of this program project. Immune parameters will also be measured for these vaccine approaches in order to select combination strategies that will enhance or compliment different arms of the immune system. The best of the vaccine strategies will be compared side by side at each site, i.e., JHUSM in the laboratories of Drs. Pardoll, Wu and Jaffee and U. Penn by Dr. Paterson, in order to control for differences in animal colonies etc.
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