Elimination of Regulatory T Cells

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DESCRIPTION (provided by applicant): The long-term goal of this application is to develop a clinically effective vaccination strategy for patients with metastatic renal cell carcinoma (RCC) by using mature dendritic cells (DC) transfected with autologous tumor RNA. In two pilot trials, we have shown that vaccination with RNA transfected DC represents a safe and effective strategy to elicit potentially therapeutic T cell responses in patients with metastatic renal and prostate cancers. More recent studies conducted in murine and human systems have demonstrated that the effects of vaccine protocols can be dramatically enhanced by the elimination of CD25+ regulatory T cell subsets preceding active immunotherapy. Here we propose to perform a clinical trial administering mature, renal tumor RNA transfected DC to patients with metastatic RCC with or without prior CD25+ regulatory T cell depletion (Aim 1). In Aim 2 of this application, we propose to analyze the vaccine-mediated and renal tumor-specific T cell responses among patients enrolled in each treatment arm (efficacy endpoint of this study). Immune monitoring will be performed by determining the presence and magnitude of tumor-specific T cells prior to and after vaccination by analyzing changes in the post-treatment cytokine profiles of activated T cells as assessed by an automated ELISPOT assay. We further propose to complement the ELISPOT data by measuring the functional capability of the in vivo generated CTL to specifically recognize and lyse autologous tumor targets. In order to optimize protocol efficacy in future trials, we will longitudinally monitor the kinetics of CD4+/CD25+ regulatory subsets prior and after vaccination with RCC RNA transfected DC. The proposed trial will allow us to proceed with sufficiently powered phase II clinical trials to directly determine the clinical efficacy of RNA transfected DC vaccines in patients with metastatic renal cell carcinoma.