Proteogenomic studies to understand mechanisms and drivers of resistance to immunotherapies

项目摘要/摘要 黑色素瘤是最致命的皮肤癌。其发病率正在上升，预计#年将新增10.6万例。 2021年的美国。免疫检查点抑制剂(ICIS)使早期和晚期的治疗发生了革命性的变化。 黑色素瘤，同时抗CTLA-4和抗PD-1单抗显示对 ~50%的患者，包括高度持久的反应。不幸的是，没有足够的生物标志物来预测 对单一药物或组合ICI和双检查点封锁的反应与显著级别相关 约55%的患者出现免疫相关不良事件(IrAEs)。我们PTRC的目标旨在解决 两个未得到满足的临床需求：(I)提高我们对ICIS耐药机制的理解，以设计更多 有效的免疫疗法和组合，以及(2)确定潜在的生物标记物以选择患者 适用于单剂免疫疗法和联合免疫疗法以及预测和监测irAEs。在我们的 临床前手臂，我们将对临床注释的治疗前活检组织进行综合蛋白质基因组分析 来自接受ICI的黑色素瘤患者。这些数据将在临床注释的背景下进行分析，以 提炼我们团队确定的黑色素瘤ICI反应的现有特征，并进一步阐明机制 与irAEs相关的ICI反应/抵抗和签名。在我们的临床部门，我们将分析临床试验 生物样品使用基于MRM的分析来确认和扩展在临床前手臂中产生的发现。

Project Summary/Abstract Melanoma is the deadliest form of skin cancer. Its incidence is on the rise with 106,000 new cases expected in the U.S. in 2021. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of early and advanced melanoma, with concurrent anti-CTLA-4 and anti-PD-1 monoclonal antibodies demonstrating a response in ~50% of patients, including highly durable responses. Unfortunately, there are no adequate biomarkers to predict response to single agent or combination ICI, and dual checkpoint blockade is associated with significant grade 3/4 immune-related adverse events (irAEs) in ~55% of patients. The goals of our PTRC are designed to address two unmet clinical needs: (i) improve our understanding of mechanisms of resistance to ICIs to design more effective immunotherapies and combinations, and (ii) identify potential biomarkers to select patients appropriately for single agent vs combination immunotherapies and to predict and monitor irAEs. In our Preclinical Arm, we will perform integrated proteogenomic analysis of clinically annotated, pre-treatment biopsies from melanoma patients who received ICI. The data will be analyzed in the context of clinical annotations to refine an existing signature of melanoma ICI response identified by our team and to further elucidate mechanisms of ICI response/resistance and signatures associated with irAEs. In our Clinical Arm, we will analyze clinical trial biospecimens using MRM-based assays to confirm & extend findings generated in the Preclinical Arm.