In this proposal we wish to explore the potential of Listeria monocytogenes, as a cancer therapeutic. We have shown using a model antigen system in BALB/c mice that a recombinant L. monocytogenes that secretes a tumor specific antigen can not only protect against tumor challenge but can also induce regression of macroscopic established tumors in an antigen-specific T cell dependent manner. 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 of 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 mouse models of gynecologic cancers in three specific aims.
In Specific Aim 1 we will construct strains of L. monocytogenes that stably express and secrete the gene products of E7 and HER-2/neu. The recipient strains for all of these genes will be wild-type strain Lm 10403s and an avirulent mutant Lm 1942 which has a defective actA gene and can no longer spread from cell to cell. The goal of Specific Aim 2 is to optimize the therapeutic effect of L. monocytogenes expressing E7 (Lm-E7) and HER-2/neu (Lm-HER-2/neu9Lm-HER- 2/neu) in murine model systems. To test the efficacy of these recombinant vaccines, we will use murine tumors that express HPV E7, made available by the Wu laboratory, or HER-2-neu, from the Jaffe laboratory, in transplantable tumor models. in addition lm-HER-2/neu recombinants will be tested for their ability to cause regression of established breast tumors in the HER-2/neu transgenic mouse model. Finally, we will compare the efficacy of the Listeria approach with a wider range of vaccine approaches developed ina the other laboratories of this program project. The best of the vaccine strategies will be compared side by side, i.e. JHUSM (in the laboratories of Drs. Pardoll. Wu and Jaffe) and U. Penn. (by Drs. Paterson and Loh) in order to control for differences in animal colonies and performance sites.
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