Proteogenomic studies to understand mechanisms and drivers of resistance to immunotherapies

项目总结/摘要 黑色素瘤是最致命的皮肤癌。其发病率正在上升，预计2010年将有106，000例新病例。 美国在2021年。免疫检查点抑制剂（ICI）彻底改变了早期和晚期 黑色素瘤，同时抗CTLA-4和抗PD-1单克隆抗体显示出对 约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 对单药或联合ICI的反应和双重检查点阻断与显著分级相关 约55%的患者发生3/4起免疫相关不良事件（irAE）。我们PTRC的目标旨在解决 两个未满足的临床需求：（i）提高我们对ICI耐药机制的理解，以设计更多 有效的免疫疗法和组合，和（ii）鉴定潜在的生物标志物以选择患者 适用于单药与联合免疫治疗，并预测和监测irAE。在我们 临床前组，我们将对临床注释的治疗前活检进行综合蛋白基因组学分析 接受ICI治疗的黑色素瘤患者。将在临床注释的背景下分析数据， 完善我们团队鉴定的黑色素瘤ICI反应的现有特征，并进一步阐明机制 ICI应答/耐药性和与irAE相关的特征。在我们的临床部门，我们将分析临床试验 使用基于MRM的分析来确认和扩展临床前研究组中产生的结果。

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.