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.

项目摘要/摘要免疫检查点抑制剂（ICI）已成为越来越多的护理标准仅在美国，每年有资格接受ICI治疗的最多230,000名患者的恶性肿瘤。尽管他们功效，ICI与病态和潜在的致命毒性有关，称为免疫相关的不良事件（伊拉斯）。皮肤伊拉斯（Ciraes）是最常报告的毒性，全部发生的20-40％迄今为止，在文献中报道了40多名不同的形态亚型的患者。虽然这些毒性的严重程度各不相同，他们对患者的生活质量有很大负担，并可能导致挽救生命的ICI疗法或对全身免疫抑制的依赖的中断可能会钝性抗肿瘤 ICIS的影响。迫切需要了解这些不良反应的方式以及为什么减少他们的影响。这项研究将研究现实世界的流行病学，下游临床意义和风险使用交叉验证的机构和人口水平数据开发这些毒性的因素。我们的第一个目标提出了一项强大的观察性研究，以确定最强的皮肤喷发与ICI疗法的关联，该疗法将被用来确定发展的临床风险因素这些事件及其下游结果。这尤其重要，因为CIRAE数据来自 ICIS在很大程度上是由非流动学家记录的，导致皮肤病表型有限。更远，目前缺乏有关Ciraes的大规模数据，并且缺乏有关什么的定义标准构成皮肤免疫疗法毒性，限制了该领域的所有研究。我们将进一步调查 CIRAE对系统性免疫抑制利用和生存的影响。我们的第二个目标将确定使用组织样品开发Cirae的种系关联从我们机构的ICI接收者那里收集。许多自身免疫性疾病具有大型种系风险变体在HLA地区的影响，我们假设HLA变异也会影响CIRAES的发展。我们的初步数据表明，Ciraes患者更可能是HLA-DR4载体，并且自身免疫性易感性的多基因风险评分（PRS）也与Ciraes显着相关。我们机构正在进行的基因分型将验证这些结果并扩大我们的风险预测识别HLA区域内外的其他遗传变异的模型。目标1和2的结果将集成到组合的临床和遗传风险分层工具中在AIM 2C中开发Cirae。由于Ciraes是最早发生的ICI毒性，并且高度相关随着非含伊拉斯的发展，这种风险分层反过来将使临床医生能够优先考虑更多针对最不可能发展毒性的患者的强化癌症疗法，并提供增强对发展这些事件的最高风险的脆弱人群的监视。