In this application the applicant wishes to explore the potential of Listeria Monocytogenes, as a cancer therapeutic. She has 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. Immunization may be oral or parenteral and immunity appears to be long lived in that two months after the tumor has been eliminated animals show no signs of regrowth and reject a further challenge of 100 times the tumoricidal dose of the same tumor. 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. monocytes as a cancer vaccine in humans, the applicant will use mouse models in three specific aims.
In Specific Aim 1 she will use the model, which she already has established and described in the preliminary studies, consisting of L. monocytogenes that secretes the influenza nucleoprotein sequence (NP) and tumor cells transduced with the same NP gene, to establish the correlates for the most effective and safest use of L. monocytogenes as a cancer therapeutic.
In Specific Aim 2 the ability of L.monocytogenes to induce immunity against a naturally expressed endogenous tumor antigen, the P1A gene product of the P815 BALB/c derived mastocytoma tumor, will be determined. The applicant will use the information derived in Specific Aim 1 to maximize the efficacy of the vaccine and a new L. monocytogenes recombinant that secretes this antigen. Finally, in Specific Aim 3, the ability of L. monocytogenes to act as a cancer therapeutic for spontaneously arising tumors in mice in vivo will be determined in a transgenic mouse model in which the SV40 T antigen is under the control of the probasin promotor resulting in prostate cancer by 10 weeks of age. SB40 T antigen is a true self antigen in the transgenic mouse since the gene is present during the maturation of the immune system. This will allow the applicant to determine the ability of a recombinant L. monocytogenes that secrets SV40T to break host tolerance to a tumor specific antigen. The applicant's long term goals are to fully explore the correlated for cancer regression, induced by the immune response to tumor antigens delivered by L. monocytogenes, prior to the exploitation of this unique therapeutic human cancer.
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