Predictive modeling of cutaneous immune checkpoint inhibitor toxicities

皮肤免疫检查点抑制剂毒性的预测模型

基本信息

批准号：
10590369
负责人：
Yevgeniy R Semenov
金额：
$ 17.6万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10590369
关键词：
Adverse event Adverse reactions Alleles Antigenic Variation Autoimmune Diseases Autoimmunity Big Data Carcinoma Case Study Clinical Clinical Data Clinical Trials Cutaneous Dana-Farber Cancer Institute Data Dermatologic Development Disease susceptibility Eligibility Determination Epidemiology Etiology Event Foundations Funding Genetic Genetic Risk Genomics Genotype HLA Antigens Immune checkpoint inhibitor Immunosuppression Immunotherapy Impairment Incidence Individual Institution Insulin-Dependent Diabetes Mellitus Interruption Life Literature Malignant Neoplasms Modeling Morbidity - disease rate Morphology Observational Study Outcome Pancreatitis Pathogenesis Pathogenicity Patients Phenotype Population Predisposition Quality of life Reporting Research Research Personnel Risk Factors Risk Marker Severities TNFRSF10A gene Time Tissue Sample Toxic effect Validation Vulnerable Populations antitumor effect cancer therapy checkpoint therapy clinical decision support clinical development clinical risk clinically relevant experience follow-up genetic association genetic risk factor genetic variant high risk immune-related adverse events insight keratinocyte large scale data mortality patient oriented patient population polygenic risk score predictive modeling risk prediction model risk stratification risk variant skin disorder standard of care tool

项目摘要

Project Summary/Abstract Immune checkpoint inhibitors (ICIs) have become standard of care for an increasing number of malignancies with up to 230,000 patients eligible for ICI therapy annually in the US alone. Despite their efficacy, ICIs are associated with morbid and potentially fatal toxicities, known as immune-related adverse events (irAEs). Cutaneous irAEs (cirAEs) are the most frequently reported toxicities, occurring in 20-40% of all treated patients with over 40 distinct morphologic subtypes reported in literature to date. Though these toxicities vary in severity, they have a considerable burden on patient quality of life and may result in interruption of life-saving ICI therapy or reliance on systemic immunosuppression that may blunt the anti-tumor effect of ICIs. There is an urgent need to understand how and why these adverse reactions occur and reduce their impact. This study will investigate the real-world epidemiology, downstream clinical implications, and risk factors for the development of these toxicities using cross-validated institutional and population-level data. Our first aim proposes a robust observational study to identify cutaneous eruptions with the strongest associations with ICI therapy, which will, in turn, be used to identify clinical risk factors for the development of these events and their downstream outcomes. This is particularly important as cirAE data from clinical trials of ICIs was largely documented by non-dermatologists with resulting limited dermatologic phenotyping. Further, there is currently a lack of large-scale data on cirAEs and an absence of definitional standards for what constitutes a cutaneous immunotherapy toxicity, limiting all research in this field. We will further investigate the impact of cirAEs on systemic immunosuppression utilization and survival. Our second aim will identify germline associations for cirAE development using tissue samples collected from ICI recipients at our institutions. Many autoimmune diseases have germline risk variants of large effect in the HLA region and we hypothesize that HLA variation will also influence development of cirAEs. Our preliminary data has demonstrated that patients with cirAEs were more likely to be HLA-DR4 carriers and that polygenic risk scores (PRSs) for autoimmunity predisposition were also significantly associated with cirAEs. Ongoing genotyping at our institution will enable validation of these results and expansion of our risk prediction models to identify additional genetic variants within and outside the HLA region. Results from Aims 1 and 2 will be integrated into a combined clinical and genetic risk stratification tool for cirAE development in Aim 2c. Since cirAEs are the earliest ICI toxicities to occur and are highly correlated with development of non-cutaneous irAEs, this risk stratification will, in turn, enable clinicians to prioritize more intensive cancer therapies for patients least likely to develop toxicity as well as to provide enhanced surveillance of vulnerable populations at highest risk of developing these events.

项目概要/摘要免疫检查点抑制剂（ICIs）已成为越来越多患者的标准治疗仅在美国，每年就有多达 230,000 名符合 ICI 治疗资格的恶性肿瘤患者。尽管他们的功效，ICIs 与病态和潜在致命的毒性有关，称为免疫相关不良反应事件（irAE）。皮肤 irAE (cirAE) 是最常报告的毒性，占所有毒性的 20-40% 迄今为止，文献报道了 40 多种不同形态亚型的治疗患者。虽然这些毒性的严重程度各不相同，它们对患者的生活质量造成相当大的负担，并可能导致中断挽救生命的 ICI 治疗或依赖全身免疫抑制可能会削弱抗肿瘤作用 ICI 的影响。迫切需要了解这些不良反应如何以及为何发生并减少他们的影响。这项研究将调查现实世界的流行病学、下游临床影响和风险使用交叉验证的机构和人口水平数据来确定这些毒性发展的因素。我们的第一个目标是提出一项强有力的观察性研究，以确定最强的皮疹与 ICI 治疗的关联，反过来，这将用于识别发展的临床危险因素这些事件及其下游结果。这一点尤其重要，因为来自临床试验的 cirAE 数据 ICI 大部分由非皮肤科医生记录，导致皮肤病表型分析有限。更远，目前缺乏关于 CIRAE 的大规模数据，也缺乏关于什么是 CIRAE 的定义标准构成皮肤免疫治疗毒性，限制了该领域的所有研究。我们将进一步调查 cirAE 对全身免疫抑制的利用和生存的影响。我们的第二个目标是使用组织样本确定 cirAE 发育的种系关联从我们机构的 ICI 接受者处收集。许多自身免疫性疾病具有较大的种系风险变异 HLA 区域的影响，我们假设 HLA 变异也会影响 cirAE 的发展。我们的初步数据表明，患有 cirAE 的患者更有可能是 HLA-DR4 携带者，并且自身免疫易感性的多基因风险评分 (PRS) 也与 cirAE 显着相关。我们机构正在进行的基因分型将能够验证这些结果并扩大我们的风险预测模型来识别 HLA 区域内外的其他遗传变异。目标 1 和 2 的结果将被整合到临床和遗传风险分层组合工具中用于 Aim 2c 中的 cirAE 开发。由于 cirAE 是最早发生的 ICI 毒性并且高度相关随着非皮肤 irAE 的发展，这种风险分层反过来将使临床医生能够优先考虑更多对最不可能发生毒性的患者进行强化癌症治疗，并提供增强的效果对发生这些事件风险最高的弱势群体进行监测。