Biomarkers of the Proinflammatory Response and Elements of Immune Suppression

项目1建立在我们的初步数据和最近的文献报告的基础上，这些文献已经确定了一系列肿瘤组织和循环血液中促炎免疫反应和免疫抑制的生物标志物，这些生物标志物在接受免疫治疗的黑色素瘤患者中具有有希望的治疗预测和疾病预后价值。作为E1609试验的一部分，将对这些进行安全性评价，该试验在可手术的IIIB/C期和M1a/B期黑色素瘤患者中测试高剂量和标准剂量的伊匹单抗辅助治疗与IFNα相比。本项目将在每个E1609试验队列中检测3个目标： 目标1：流通。(1a)循环细胞群：检验基线和/或治疗早期IFNg+ CD 4+和IFNg+ CD 8+抗原特异性T细胞免疫以及特异性宿主抑制因子（确定的调节性T细胞和髓源性抑制细胞群）与临床结果相关（RFS和OS），（Ib）循环血清生物标志物：检验基线和/或早期治疗促炎细胞因子和趋化因子谱与临床结果相关的假设。 目标二：肿瘤和肿瘤微环境：首先，检验治疗前促炎性肿瘤微环境（免疫相关基因的高基线表达水平）与临床结局（RFS和OS）相关的假设。作为次要子目标，我们将检测肿瘤突变状态（BRAF、NRAS和野生型状态）与临床结局的相关性。我们还将评估免疫相关基因甲基化水平的预测价值。 目标3：基于常见系统生物学，将开发一个整体模型分析，以将目标1和2中的目标标志物联系起来（将循环中的重要标志物与肿瘤微环境中的标志物联系起来），其中我们假设将在每个试验组中鉴定和验证生物标志物的促炎治疗预测特征。我们期望基于共同系统生物学的ipilimumab和HDI的重叠预测模型。

Project 1 builds on our preliminary data and recent reports in the literature that have identified a series of biomarkers of a pro-inflammatory immune response and of immunosuppression in both tumor tissue and in circulating blood that have promising therapeutic predictive and disease prognostic value in melanoma patients treated with immunotherapy. These will be simultaneoulsy evaluated as part of E1609 trial testing adjuvant ipilimumab at high dose and standard dose versus IFNα in patients with operable stage IIIB/C and M1a/b melanoma. This project will have 3 aims to be tested within each of the E1609 trial cohorts: Aim 1: Circulation. (1a) Circulating cellular populations: test the hypothesis that baseline and/or early on-treatment IFNg+CD4+ and IFNg+CD8+ antigen specific T-cell immunity as well as specific host suppressor elements (defined populations of regulatory T cells and myeloid-derived suppressor cells) correlate with clinical outcome (RFS and OS), (lb) Circulating serum biomarkers: test the hypothesis that baseline and/or earty on-treatment pro-inflammatory cytokine and chemokine profiles correlate with clinical outcome. Aim 2: Tumor and tumor microenvironment: First, test the hypothesis that a pretreatment, pro-inflammatory, tumor microenvironment (high baseline expression levels of immune-related genes) correlates with clinical outcome (RFS and OS). As secondary sub-aims, we will test the association of the tumor mutational status (BRAF, NRAS and wild-type status for both) and clinical outcome. We will also assess the predictive value of the methylation levels of immune-related genes. Aim 3: Based on the common systems biology, an overall model analysis will be developed to link markers of interest in Aims 1 and 2 (linking significant markers in the circulation with those in the tumor microenvironment) where we hypothesize that a pro-inflammatory therapeutically predictive signature(s) of biomarkers will be identified and validated within each of the trial arms. We expect overlapping predictive models for ipilimumab and HDI based on the common systems biology.