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

• 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
• 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

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.

项目总结/摘要 免疫检查点抑制剂（ICI）已成为越来越多的患者的标准治疗。 仅在美国，每年就有多达230，000名患者符合ICI治疗的条件。尽管他们 在疗效方面，ICI与病态和潜在致死性毒性相关，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，发生率为20-40% 迄今为止，在文献中报告了超过40种不同形态学亚型的治疗患者。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治疗或依赖可能减弱抗肿瘤作用的全身免疫抑制 ICs的影响。我们迫切需要了解这些不良反应是如何以及为什么发生的， 他们的影响这项研究将调查现实世界的流行病学，下游临床意义和风险 使用交叉验证的机构和人群水平的数据，这些毒性的发展因素。 我们的第一个目标是提出一个强大的观察性研究，以确定最强烈的皮疹 与ICI治疗的相关性，这反过来将用于识别发展的临床风险因素， 这些事件及其下游结果。这一点尤其重要，因为cirAE的临床试验数据 ICI主要由非皮肤科医生记录，导致皮肤表型有限。此外，本发明还 目前缺乏关于cirAE的大规模数据，也没有关于什么是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对全身免疫抑制剂利用和生存的影响。 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接收者那里收集。许多自身免疫性疾病具有大的生殖系风险变体， 在HLA区域的影响，我们假设HLA变异也会影响cirAE的发展。我们 初步数据表明，cirAE患者更可能是HLA-DR 4携带者， 自身免疫易感性的多基因风险评分（PRS）也与cirAE显著相关。 我们机构正在进行的基因分型将使这些结果得到验证，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的结果将整合到临床和遗传风险分层工具中 在目标2c中开发cirAE。由于cirAE是最早发生的ICI毒性，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 为最不可能产生毒性的患者提供强化的癌症治疗， 监测最有可能发生这些事件的弱势群体。