LOCAL MODULATION OF DENDRITIC CELLS FOR MECHANISTIC INSIGHT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have developed a straightforward antigen-specific anti-tumor immunotherapy, targeting the non-mutated "self" tumor associated antigen (TAA), neu, in a stringent rat breast cancer model that uses a novel alphavirus-derived replicon particle (VRP) vector with tropism for dendritic cells (DCs), the most potent immunostimulatory antigen-presenting cell. This immunotherapy elicits significant anti-tumor immune responses including the ability to cure a proportion (?20-40%) of animals with pre-existing tumor; a level of activity rarely reported (only four reports) in comparable anti-tumor vaccine strategies targeting single, true "self" TAAs. Although our cure rate is not 100%, no animals eliminating their tumors relapsed and significantly, tumors that grew in the setting of antigen-specific therapy had down-regulation of TAA expression. This level of activity, although promising, is less than optimal suggesting that mechanistic insights leading to identification of methods to enhance activity would accelerate the translation of this promising anti-tumor immunotherapy into the clinical arena and result in greater impact for cancer patients. The Central Hypothesis of this study is: DC tropism is critical for the potent activity of VRP-based anti-tumor immunotherapies and is subject to methods to enhance immunotherapy activity. The following Specific Aim will be the initial step in testing this hypothesis: Specific Aim: Define the role of DC tropism in the activity of VRP-based anti-tumor immunotherapy. This aim will address questions that are important for understanding the mechanisms by which this VRP vector system elicits potent anti-tumor immune responses. We will specifically employ maneuvers to increase the local availability of DCs for VRP transduction with the prediction that this will result in enhanced anti-tumor immunity. We will also deplete local DCs prior to VRP administration with the prediction that immunotherapy activity will be abrogated. 1. Modulate local peripheral DC populations by recruiting immature DCs to peripheral sites with GM-CSF or the monocyte/DC-specific chemokine CXCL14 and depleting immature DCs with Imiquimod. 2. Examine the effect of local DC modulation on in vivo VRP transduction efficiency and DC activation. 3. Evaluate the effect of local DC population modulation on the efficacy of VRP-based immunotherapy. These studies will provide the preliminary data to support an expanded specific aim and research plan to 1) improve the VRP immunotherapy, 2) further explore VRP mechanistic questions, and 3) provide data to expedite clinical translation and clinical study.