This research program was initiated following observations that a whole body exposure to a mild, fever-like hyperthermia (39.5 degree C for 6-8 hours, i.e., """"""""physiological hyperthermia""""""""), resulted in alternations in lymphocyte structure, inhibition of tumor growth and increased tumor cell apoptosis in murine models. While this response is not in itself, curative, the fact that such a mild treatment would have any anti-tumor activity at all was somewhat unexpected. The major hypothesis being tested to explain these observations is that this fever-like treatment enhances the immune response or facilitates the immunological rejection of tumors. From this hypothesis, the investigators predict that the moderate hyperthermia protocol will synergize with other therapies (vaccines, adoptive T cell therapy or cytokine treatments) that stimulate the anti-tumor immune response. Their preliminary and published data strongly support these assumptions. The major goal of this renewal application continues to be a determination of the molecular and immunological mechanism(s) underlying the anti-tumor effects of physiological hyperthermia so that its usefulness can be fully exploited in the clinic. Since the immune system is composed of multiple systems and cells upon which physiological hyperthermia could exert its effects, the investigators have continued to evaluate molecular endpoints in Aims 1 and 2 that would be important for all aspects of immune response: gene and protein expression, and lymphocyte membrane organization. Moreover, the investigators have chosen to evaluate functional endpoints that represent a convergence of many important components and levels of the immune system, i.e., immune response to several specific tumor antigens (Aim 3). Finally, they have chosen to evaluate whether whole body hyperthermia would be synergistic with other immunotherapies, such as vaccines, T cell or cytokine administration (Aim 4). All of these aims are logically derived from the progress made by the investigators in the first period of funding. Moreover, compelling preliminary data has been obtained strongly supporting the use of fever-like hyperthermia in combination with vaccines or cytokines for the treatment of cancer. With a better understanding of the molecular and cellular mechanisms underlying the anti-tumor effects of physiological heating, the investigator hopes to more rationally define how this approach can be utilized clinically. Since a Phase I trial using fever-like hyperthermia alone (to demonstrate its safety before combining it with other treatments), is just being completed the investigators will be poised to apply the information obtained from the studies described in the present proposal to the rapid development of new Phase I/II trials at this Institute.
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