RECOMBINANT LISTERIA VACCINES FOR MELANOMA

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Listeria monocytogenes is a gram positive bacterium that is able to enter host cells, escape from the endocytic vesicle, multiply within the cytoplasm and spread directly from cell-to-cell without encountering the extracellular milieu. The ability to gain access to the host cell cytosol allows proteins secreted by the bacterium to efficiently the MHC class I antigen processing and presentation pathway leading to the induction of CD8+ cytotoxic T cells (CTL). We developed a genetic system for expression and secretion of foreign antigens by L. monocytogenes. Recombinant vaccine strains expressing the lymphocytic choriomeningitis virus (LCMV) nucleoprotein (NP), or a specific MHC class I restricted NP epitope, are able to induce LCMV specific CD8+ cytotoxic T lymphocyte (CTL) responses in mice following vaccination. These strains confer antiviral protection as indicated by the ability of immunized mice to efficiently clear LCMV infection. Listeria strains that express the E11 protein cottontail rabbit papillomavirus (CRP) have also been constructed. Immunization of rabbits with these recombinants causes regression of CRPV induced papillomas and protection from carcinoma. These and other results demonstrate the utility of Listeria vaccine strains for inducing antiviral and anti-tumor immunity. Our objectives are to explore the utility of recombinant Listeria strains as anti-tumor vaccines and determine optimal strategies for attenuation and antigen delivery. The specific aims are to: 1. Construct L. monocytogenes vaccine strains expressing tumor rejection antigens. L. monocytogenes strains expressing the melanoma associated tumor rejection antigens gp100, MART1, TRP2, or an H-2K/b restricted TRP2 181-188 epitope will be constructed. 2. Determine the effects of prophylactic or therapeutic administration of recombinant Listeria vaccine strains on tumor establishment, growth and regression. Two murine tumor models will be used to test vaccine efficacy. 3. Construct Listeria innocua vaccine strains and compare their immunogenicity with wild type and attenuated L. monocytogenes. L. innocua is a non-pathogenic member of the Listeria genus. By transferring genes from L. monocytogenes, we will attempt to construct chimeric strains that are immunogenic yet avirulent.