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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.

项目总结/文摘