Evidence is provided that a 2 degree C (6-8 hr) elevation of body temperature results in substantial apoptosis of human tumors growing in a SCID mouse chimeric model and as well in transplantable murine tumors grown in Balb/c mice. This whole body hyperthermia (WBH) protocol differs from conventional WBH and local hyperthermia protocols in that it employs a much lengthier heat exposure at lower temperatures and thus, approximates the thermal element of a normal fever. Understanding and eventually exploiting the mechanism(s) by which this mild heat exposure exerts such significant anti-tumor activity may provide an additional approach in the treatment of cancer. The preliminary data have led to the hypothesis that fever-range WBH can inhibit tumor growth by its effects on the immune response against tumors; a corollary to this hypothesis is that by using additional methods which also stimulate the anti-tumor immune response in combination with whole body hyperthermia, we may be able to significantly enhance the anti-tumor effects over that seen with any one treatment alone. The overall goal of this application is to conduct a series of experiments designed to test these possibilities. Several lines of evidence suggest that one important mechanism by which WBH stimulates the immune system involves a cytolytic response, i.e., the action of natural killer (NK) lymphocytes, the predominant effector cell of the innate immune response, and cytolytic T lymphocytes, effector cells of the adaptable immune response; experiments designed to support this assumption, using both human and murine tumor systems, will be conducted as part of Aim 1. Other data suggest that there is also a cytokine response to WBH, and in Aim 2, the role of host cytokines (including those that can stimulate tumor reactive T lymphocytes and NK cells, and which may be induced by the hyperthermia treatment itself, will be assessed. The data obtained in these first two aims will be useful in Aim 3, where we will conduct studies to determine if the effects of fever-range WBH on tumor growth can be enhanced by combination with immunotherapies including specific vaccine therapy and addition of exogenous cytokines and effector cells. Importantly, an enhancement of the anti-tumor effects of WBH with the addition of IFN-g has already been observed in Preliminary Studies. The existence of several appropriate model systems, in which various assumptions regarding the mechanisms of action of fever-range WBH can be tested at the preclinical, cellular and molecular levels, combined with the multidiciplinary approach of this experienced group of investigators, will provide an excellent scientific foundation for clinical trials of fever-range whole body hyperthermia in the near future.
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