Elimination of Regulatory T Cells

描述（由申请方提供）：本申请的长期目标是通过使用自体肿瘤RNA转染的成熟树突状细胞（DC）为转移性肾细胞癌（RCC）患者开发临床有效的疫苗接种策略。在两项初步试验中，我们已经表明，用RNA转染的DC接种疫苗是一种安全有效的策略，可以在转移性肾癌和前列腺癌患者中引发潜在的治疗性T细胞应答。最近在鼠和人系统中进行的研究表明，在主动免疫治疗之前消除CD 25+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，给予成熟的，肾肿瘤RNA转染的DC转移性RCC患者与或没有事先CD 25+调节性T细胞耗竭（目标1）。在本申请的目的2中，我们建议分析每个治疗组入组的患者中疫苗介导的和肾肿瘤特异性T细胞应答（本研究的疗效终点）。通过分析自动化ELISPOT试验评估的活化T细胞的治疗后细胞因子谱的变化，确定疫苗接种前后肿瘤特异性T细胞的存在和大小，进行免疫监测。我们进一步建议通过测量体内产生的CTL特异性识别和裂解自体肿瘤靶的功能能力来补充ELISPOT数据。为了在未来的试验中优化方案效力，我们将纵向监测接种RCC RNA转染DC前后CD 4 +/CD 25+调节亚群的动力学。拟议的试验将使我们能够进行足够有力的II期临床试验，以直接确定RNA转染的DC疫苗在转移性肾细胞癌患者中的临床疗效。

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.