The overall goal of the studies outlined in this application is to develop localized immunotherapeutic strategies for the elicitation of systemic tumor specific immunity. The appplicant and others have recently demonstrated mechanisms by which murine and human tumors may escape immune recognition and elimination and have begun to develop strategies for overcoming these limitations. Based on these findings, and the mechanistic analysis outlined below, they will develop strategies to specifically enhance immune recognition and the generation of systemic cell-mediated anti-tumor responses. Towards this end, they will: 1. Assess the interaction between tumor and the host immune cells in patients with transitional cell carcinoma of the bladder; 2. Assess the effects of inhibition of IL-10 on TCC growth and antigen expression; 3. Assess the role of tumor associated cytokines and expression of MHC and non-MHC surface antigens in enhancing tumor specific immunity; and 4. Design and develop in vivo localized therapeutic strategies to stimulate the development of systemic tumor specific immune responses following intralesional and/or intravesical manipulation. If successful, the studies outlined in this application will: 1) Significantly enhance our understanding of the regulation of human antitumor immunity; 2) Determine the effects of enhanced antigen presentation and manipulation of tumor-immune parameters on the development of immunity; and therefore allow the development and in vitro testing of reagents for the in situ manipulation of the above mechanisms(s). While the proposed studies focus on the development of localized therapeutic strategies for TCC, the information obtained will have significant impact on the development of more traditional tumor-vaccine strategies and will be readily translatable to other tumors approachable locally. Based on our approach, strategies identified in these studies will be rapidly translatable to clinical trial.
