TOWARDS PRECISION IMMUNO-ONCOLOGY: UNRAVELING THE GENOMIC DETERMINANTS AND MECHANISMS UNDERLYING IMMUNOTHERAPY EFFICACY AND RESISTANCE

迈向精准免疫肿瘤学：揭示免疫治疗功效和耐药性背后的基因组决定因素和机制

• 批准号: 10201107
• 负责人: Timothy An-thy Chan
• 金额: $ 16.1万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10201107
• 关键词: 2019-nCoV; Address; Adult Respiratory Distress Syndrome; Advanced Malignant Neoplasm; Affect; Age; Alleles; COVID-19; Cancer Patient; Cessation of life; Clinic; Clinical; Common Neoplasm; Contracts; Data; Data Set; Disease; Environment; General Population; Genes; Genetic; Genetic Determinism; Genomics; Genotype; Goals; Health system; Hospitals; Immune; Immunity; Immunocompromised Host; Immunologics; Immunooncology; Immunotherapy; Infection; Malignant Neoplasms; Medical; Methods; Molecular; Morbidity - disease rate; Outcome; Patients; Population; Process; Recovery; Research; Resistance; Respiratory physiology; Severities; Severity of illness; Somatic Mutation; Symptoms; Ventilator; Virus; Work; base; cancer genetics; clinical sequencing; cohort; coronavirus disease; cytokine; driver mutation; high risk; insight; mortality; mortality risk; multidisciplinary; novel; outcome forecast; pandemic disease; tumor

The SARS-CoV2 virus has caused a worldwide pandemic resulting in a great deal of morbidity and many deaths. Infection with this virus causes the COVID-19 disease, which can result in acute respiratory distress syndrome. Even in patients that survive the disease, the virus can cause significant morbidity, require ventilator support for respiratory functions, and necessitate a prolonged recovery process. Interestingly, severe sequelae of COVID-19 is not uniformly distributed across the population. While some people are asymptomatic or have mild symptoms, others can rapidly succumb to the disease. Some early data have been generated that shows that cancer patients may be particularly harmed by SARS-CoV2 infection7,8. However, the differential effects of the infection on patients with different cancers and how genetic factors influence outcomes is unknown. The overall goal of the work proposed in this supplement is to characterize the effects of critical genetic variables on COVID-19 prognosis in cancer patients. The central hypothesis of this proposal is that specific genetic features - HLA genotype and distinct somatic mutations – can strongly influence the severity of COVID19 infection. We will pursue 2 specific aims. In Aim 1, we will elucidate the effects of HLA diversity on prognosis and severity of COVID19 infection in cancer patients. Based on our preliminary data, the working hypothesis here is that HLA molecular diversity will affect prognosis in COVID19 patients with advanced cancers. We have previously developed a highly versatile method to quantitate HLA diversity called HLA evolutionary diversity (HED). We will characterize the effects of HED and HLA allelic effects on COVID severity in cancer patients. In Aim 2, we will characterize the effects of immunologically active driver mutations in cancer patients with common tumors. It is well known that certain driver genes can affect both the tumor immune environment as well as systemic immunity commonly through cytokine dysregulation. Our hypothesis here is that immunologically active cancer drivers may affect COVID19 clinical course. Using our large cohorts of cancer patients with clinical sequencing available, we will examine the effects of common somatic driver mutations on COVID19 prognosis. The combination of our aims will provide novel and impactful insights into the effects of genetic determinants on the clinical course of cancer patients who contract COVID19

SARS-CoV 2病毒已经引起了世界范围的大流行，导致了大量的发病率和许多死亡。感染这种病毒会导致COVID-19疾病，可导致急性呼吸窘迫综合征。即使在存活下来的患者中，病毒也会导致显著的发病率，需要呼吸机支持呼吸功能，并且需要延长恢复过程。有趣的是，COVID-19的严重后遗症在人群中的分布并不均匀。虽然有些人没有症状或症状轻微，但其他人可能很快死于这种疾病。一些早期数据显示，癌症患者可能特别受到SARS-CoV 2感染的伤害。然而，感染对不同癌症患者的不同影响以及遗传因素如何影响结果尚不清楚。本补充文件中提出的工作的总体目标是描述关键遗传变量对癌症患者COVID-19预后的影响。该建议的核心假设是，特定的遗传特征- HLA基因型和不同的体细胞突变-可以强烈影响COVID 19感染的严重程度。我们将追求两个具体目标。在目的1中，我们将阐明HLA多样性对癌症患者COVID 19感染的预后和严重程度的影响。根据我们的初步数据，这里的工作假设是HLA分子多样性将影响COVID 19晚期癌症患者的预后。我们以前已经开发了一种高度通用的方法来定量HLA多样性称为HLA进化多样性（HED）。我们将描述HED和HLA等位基因效应对癌症患者中COVID严重程度的影响。在目标2中，我们将描述具有常见肿瘤的癌症患者中免疫活性驱动突变的影响。众所周知，某些驱动基因通常可以通过细胞因子失调影响肿瘤免疫环境以及全身免疫。我们的假设是，免疫活性的癌症驱动因素可能会影响COVID 19的临床进程。使用我们的大型癌症患者队列和可用的临床测序，我们将检查常见的体细胞驱动突变对COVID 19预后的影响。我们的目标相结合，将为遗传决定因素对感染COVID 19的癌症患者的临床过程的影响提供新的和有影响力的见解。