The objective of this study is to determine whether host circadian rhythms influence the efficacy of tumor immunotherapy with rTNF, rIL-1beta, CY, or sublethal gamma-irradiation. These immunomodulators are known to induce tumor regression by enhancing, or facilitating, the expression of antitumor immunity rather than by a direct effect on the tumor itself. In addition, each of these agents is in contact with the immune system for only a short time. It is hypothesized that the efficacy of a minimum therapeutic dose with these immunomodulators will vary in a circadian-dependent fashion because of (a) differences in the rate of clearance of the immunomodulator from the blood and/or (b) differences in the responsiveness or susceptibility of target tissues to the immunomodulator at different times. Experiments will be designed initially to determine whether there are statistically significant differences in the therapeutic efficacy of immunotherapy with these immunomodulators given at different times during the circadian cycle. Each agent will be evaluated chronobiologically in age-matched mice at 3 different times during the year in order to establish reproducibility of rhythm parameters and to detect potential circannual rhythms. Additional experiments will focus on those agents with statistically verified circadian rhythms in therapeutic efficacy, to determine whether circadian-dependent variation in therapeutic activity of the immunomodulator is due to physiologic rhythms that influence the serum half-life of the agent in a tumor-bearing host. Published procedures for measuring TNF, IL-1 and CY in body fluids will be used. In addition, these agents can be radiolabeled in order to monitor circadian-determined variations in their tissue distribution, metabolism, and/or excretion. By tailoring the administration of TNF, IL-1beta, CY or gamma-irradiation to host biorhythms it may be possible to optimize the effect of these immunomodulators on antitumor effectors or suppressors and to improve the efficacy of tumor immunotherapy. The success of this approach will depend, however, on the use of appropriate models of immunologically mediated tumor regression about which knowledge exists concerning the contributions of positive and negative regulation on host immunity at the time of treatment.
