This revised Program Project Application describes the research objectives of three experienced investigators who are working on the long-term goal of improving immunotherapy of cancer by working within the unifying theme of the study of heat and heat shock proteins and their effects on the immune response. The overall hypothesis is that both thermal stimuli and heat shock proteins, if better understood at the immunological level, can be manipulated therapeutically to promote the regression of human malignancies and allow induction of long-lived immune responses. This hypothesis has as its roots the recognition by the Project Leaders of the fundamental, long-conserved biological significance that both hsps and fever have on survival and the regulation of the immune response. The overall research efforts are focused toward determining whether hsps and/or thermal stimuli can serve as adjuvants and result in changes in well-defined immunological parameters that are known to be important in development of effective anti-tumor immunity. These include vaccine potency and anti-tumor immune responses, and homing of effector cytolytic T cells to the site of tumor. These analyses will thus provide the foundation for future studies in humans. The three Projects address the following questions in an integrated fashion: How can we improve the potential of heat shock proteins td serve as part of cancer vaccines? 2. How does the thermal environment of the immune system influence the efficacy of vaccines and adoptive T cell therapy of cancer? How do thermal stimuli influence clinically measurable immune parameters such as alterations in the adhesive and homing potential of cytotoxic immune effector cells, and cytokine function? These projects will be supported by two scientific Cores and an Administrative Core that will contribute to the successful progression of efforts in each of these three projects. This Program application represents the recognition that the Project Leaders need to work together as a team to enhance the more rapid achievement of the ultimate goal to develop novel approaches to cancer therapy. This group has already interacted extensively at the scientific level and has developed clinical collaborations, thereby providing the experience needed to realistically bring future laboratory findings to the cancer clinic.
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