Elimination of Regulatory T Cells

描述(申请人提供)：这项申请的长期目标是开发一种临床有效的疫苗接种策略，通过使用转染自体肿瘤RNA的成熟树突状细胞(DC)来治疗转移性肾细胞癌(RCC)。在两个试点试验中，我们已经证明，在转移性肾癌和前列腺癌患者中，接种RNA转染树突状细胞是一种安全有效的策略，可以诱导潜在的治疗性T细胞反应。最近在小鼠和人类系统中进行的研究表明，在主动免疫治疗之前消除CD25+调节性T细胞亚群可以显著增强疫苗方案的效果。在这里，我们建议进行一项临床试验，对有或没有CD25+调节性T细胞耗尽的转移性肾癌患者应用成熟的肾肿瘤RNA转基因DC(目标1)。在这项应用的目标2中，我们建议分析在每个治疗组登记的患者中疫苗介导的和肾肿瘤特异性T细胞反应(这项研究的疗效终点)。免疫监测将通过分析治疗后激活的T细胞的细胞因子图谱的变化来确定接种前后肿瘤特异性T细胞的存在和数量，如自动ELISPOT分析所评估的那样。我们进一步建议通过测量体内产生的CTL特异性识别和溶解自体肿瘤靶点的功能能力来补充ELISPOT数据。为了在未来的试验中优化方案的有效性，我们将纵向监测RCC RNA转基因DC接种前后CD4+/CD25+调节亚群的动力学。拟议的试验将使我们能够继续进行动力充足的II期临床试验，以直接确定RNA转基因DC疫苗对转移性肾癌患者的临床疗效。

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.