Research Project
7638964
DESCRIPTION (provided by applicant): Recent progress in molecular and cellular immunology has advanced our understanding of tumor-host interactions and opened extraordinary opportunities for the development of anti-tumor immunotherapies. The identification of tumor antigens over the last decade for many tumors, including ovarian, has laid the foundation for the development of tumor-specific vaccines. Ovarian cancer has one of the highest mortality rates among women with gynecological malignancy, approximately 14,000 cancer deaths per year. Women with late-stage disease have a 2-year relapse rate of more than 50%, with a five-year survival rate of less than 50%. A variety of immunotherapy regimens are currently being evaluated in the clinic for the treatment of advanced ovarian cancer, utilizing either monoclonal antibodies or active immunization strategies. Ovarian-specific tumor antigens include (but are not limited to) HER-2, CA125, NY-ESO-1, MUC-1, and mesothelin. However, a larger panel of validated ovarian cancer antigens is needed in addition to potent vaccine vectors to ensure the success of the therapeutic option. Listeria is an intracellular bacterium that elicits a vigorous innate immune response that leads to priming of potent CD4+/CD8+ T cell mediated immune responses. Immunization with Listeria expressing heterologous associated antigens has striking activity in animal models of both infectious disease and cancer, and has been tested in healthy volunteers. Novel ovarian cancer-associated antigens have been recently identified by differential and high through put sequencing technologies to identify MHC class I and II epitopes specifically associated with tumor cells. This application will focus on the development of an immunotherapeutic approach based on polyepitope Listeria vectors for ovarian cancer. We propose to evaluate and construct a panel of attenuated Listeria strains expressing CD8+ T cell epitopes specific to ovarian cancer. The Listeria strains will be analyzed for optimal expression, programming of MHC class l-restricted antigen presentation, and the ability to prime tumor specific immunity in vitro and in vivo (HLA-A2 transgenic mice).
