Localized immunotherapeutic approaches to cancer have been effective in treating tumors such as melanoma and bladder carcinoma, although the mechanism of action of such therapies as intravesical or intralesional BCG has eluded definition. While localized mechanisms which result in tumor elimination contribute to therapeutic success, optimal anti-tumor effectiveness, particularly at disseminated tumor sites, requires the development of systemic immunity which must be the goal of any new therapy. Using a murine model of orthotopic bladder tumor growth, the studies outlined in this proposal are aimed at developing strategies for the development of systemic anti-tumor immunity following immunotherapy designed to result in lymphocyte activation at the tumor site. The overall hypothesis of the proposal is that by modulating the immune milieu at the local tumor site, and thus recruiting antigen-presenting and effector cell populations, it will be possible to engender a systemic tumor specific immune response. The result would be to eliminate both localized and disseminated tumor. Towards this end, studies have been designed which use intravesical BCG, in-vivo cytokine manipulation, and our newly developed recombinant vaccinia gene therapy approaches to assess the effectiveness of manipulating tumor antigenicity and the overall cytokine/lymphokine milieu on developing tumor-specific immunity. While these studies utilize a bladder tumor model, the results obtained, particularly using our new vaccinia methodology, will be directly applicable to a variety of tumors, allowing in-situ manipulation of the localized immune 'environment' and, we anticipate, the generation of systemic anti-tumor immunity.
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