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肿瘤组织和循环血液中促炎免疫反应和免疫抑制的一系列生物标志物，这些生物标志物在接受免疫治疗的黑色素瘤患者中具有良好的治疗预测和疾病预后价值。这些将同时作为E1609试验的一部分进行评估，测试高剂量和标准剂量的辅助ipilimumab与IFNα在可手术iii期ib /C和M1a/b黑色素瘤患者中的作用。该项目将有3个目标在每个E1609试验队列中进行测试：

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.