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Grant Abstract

Grant Number: 5P50AT002779-04
Project Title: Development of Biomarkers for Study of Botanical Immunomodulators in Humans

Abstract: The immune system has the capacity to mediate specific protection against pathogens and tumors. Therefore there is great interest in methods to harness the immune system for therapeutic benefit. Many botanicals are commonly utilized in humans for their putative immune-modulatory effects. However, the effects of these agents on specific immune responses in humans, both in vitro and particularly in vivo, remain unclear. In parallel with investigations described under Projects by Livingston, Cheung, and Pamer, we seek to define the effects of botanicals on the human immune response. Accomplishment of this objective will guide the design of larger clinical trials in the future and is essential to the translation of preclinical research findings to the clinic. The objective of Project by Cassileth is to identify and characterize the effects of the selected botanicals on human immune response in vitro and in vivo. Our working hypothesis is that some effects of oral botanicals on the human immune system can be modeled in vitro using quantitative assays, that these assays may be useful as surrogate markers of botanical effects in vivo, and that the detection of measurable biologic effects on the immune system after supplementation in vivo will be important both for defining their activity and for understanding their mechanism of action. We will test the effects of selected core botanicals on peripheral blood mononuclear cells from healthy volunteers. In parallel, immune modulatory effects of selected botanicals will also be tested in vivo in the context of early phase clinical trials to define human in vivo biomarkers. The first trial will be conducted in healthy volunteers in years 1-2. Effects on innate and adaptive immunity will be evaluated. In the later years of the study period, data from projects by Livingston, Cheung, and Pamer will be utilized to design early-phase clinical trials to test the effects of botanicals in disease settings. As a whole, these data will provide the framework for optimal evaluation of immunogenicity and biologic effects of these agents, and their combination with other therapies (eg, monoclonal antibodies or vaccines) in cancer patients. The specific aims are: 1. To characterize the effects of selected botanicals on human immune response in vitro; 2. To evaluate the immunomodulatory effects of Maitake D fraction and assess dose response in a small early phase placebo-controlled, double-blind clinical study in healthy volunteers; 3. To confirm the findings made in Projects by Livingston, Cheung, and Pamer in the context of 2 early-phase clinical trials in appropriate disease settings in human populations.

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