The goal of this project is to develop effective molecularly-defined immune adjuvants for active immunizationagainst cancer. Although tolerance to cancer is reversible, immunization against cancer antigens facessubstantial hurdles related to tolerance and immune regulation. Potent immune adjuvants will be necessaryfor successful active immunization against cancer antigens, which are inherently poorly immunogenic. Weapply recent knowledge about molecules that regulate growth, activation and survival of innate and acquiredimmune cells to study adjuvant strategies and underlying mechanisms. We use genetic adjuvants (plasmidDNA incorporating Fc domains of IgG) combined with DNA vaccines against cancer antigens. DNAencoding cytokines have been carefully selected for analysis based on results of extensive preliminaryscreening and on our understanding about how these molecules regulate activation and survival of innateand acquired immune cells.
Specific aim 1 is built on experimental results from our screens showing thatDNA encoding an IL-12/Fc fusion molecule is most effective at enhancing T cell responses and tumorimmunity. A phase I clinical trial is proposed to assess safety of IL-12/Fc DNA and compare the relativeimmunologic efficacy of vaccination with tyrosinase DNA plus IL-12/Fc DNA adjuvant to tyrosinase DNAalone in patients with stage III melanoma.
Specific aim 2 examines why ligation of Fc domains to cytokinesmarkedly increases adjuvanticity while unexpectedly decreasing their bioavailability. Genetic approachesare used to address the hypothesis that adjuvant effects are amplified by interactions with Fc receptors oninnate immune cells.
Specific aim 3 studies DNA adjuvants combined with vaccination in treatment modelsof melanoma, including treatment in a transgenic model that develops de novo melanoma.
Sub aimsi nvestigate a) the role of IFNgamma produced by NK cells for adjuvanticity by cytokine and cytokine/Fc cDNAs,and b) adjuvant effects of IL-23 DNA, which is strongly implicated in the pathogenesis of inflammatoryautoimmune diseases.
Specific aim 4 investigates the role of cytokine DNA adjuvants for potentiatingantigen-specific responses elicited by vaccination during homeostatic recovery of the immune system afternon-myeloablative treatments. The overall goal is to develop the most potent DNA adjuvants that can beapplied to vaccines delivered during homeostatic recovery.
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