Understanding Inflammatory Arthritis due to Immune Checkpoint Inhibitors

了解免疫检查点抑制剂引起的炎症性关节炎

基本信息

批准号：
10680524
负责人：
Laura Christine Cappelli
金额：
$ 15.58万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-16 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10680524
关键词：
Address Adrenal Cortex Hormones Alleles Antibodies Area Arthritis Autoantibodies Autoimmune Autoimmune Diseases Award Biological Assay Characteristics Clinical Clinical Data Clinical Investigator Collaborations Collection Data Data Science Degenerative polyarthritis Development Diagnosis Disease Dose Epitopes Evaluation Event Family history of Fostering Foundations Future Goals Health IL17 gene Immune Immune checkpoint inhibitor Immunogenetics Immunologic Factors Immunosuppression Immunotherapy Inflammatory Inflammatory Arthritis Interleukin-6 Joints Knowledge Laboratories Literature Machine Learning Malignant Neoplasms Mentors Methods Modeling Monitor Morbidity - disease rate Myositis Oncology Operative Surgical Procedures Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Predictive Factor Prognosis Public Health Schools Research Research Personnel Resolution Resources Rheumatism Rheumatoid Arthritis Rheumatology Risk Risk Factors Science Serum Sjogren&apos s Syndrome Specialist Subgroup Surveys Sushi Domain Syndrome T-Lymphocyte Techniques Time Trauma Treatment Protocols Vasculitis Visit active method anti-PD-1 anti-tumor immune response cancer immunotherapy cancer therapy career development checkpoint therapy clinical heterogeneity clinical phenotype clinical risk clinically relevant cohort cytokine data standards experimental study human leukocyte antigen testing immune-related adverse events improved insight meetings negative affect patient stratification potential biomarker prospective response rheumatologist risk stratification skills symposium targeted treatment therapeutic target translational scientist treatment response tumor tumor immunology

项目摘要

Project Summary/Abstract The major goals of this proposal are to attain skills required to be an independent clinical and translational researcher in rheumatology and to enhance understanding of a new rheumatic disease, inflammatory arthritis (IA) due to immune checkpoint inhibitors (ICIs). ICIs are revolutionizing cancer treatment but also cause immune related adverse events. ICI-induced IA is the immune related adverse event most likely to be encountered by rheumatologists. ICI-induced IA causes significant morbidity, is clinically heterogeneous, and can persist after ICI cessation. The proposed project will utilize a group of well characterized patients with ICI- induced IA and ICI-treated control patients who do not develop IA to address several important questions. First, the clinical heterogeneity within ICI-induced IA will be evaluated and factors that predict persistence of IA beyond cessation of ICI therapy will be established. Next, clinical and immunogenetic risk factors for developing ICI-induced IA will be determined. Finally, serum cytokine profiles and autoantibodies before and after ICI treatment will be compared in patients with ICI-induced IA and control patients who are treated with ICIs and do not develop IA. These experiments will address key knowledge gaps for this emerging clinical entity. Specifically, defining relevant clinical subgroups will allow for differential monitoring and treatment of patients. Understanding risk factors for development of IA will allow for risk stratification of patients prior to therapy. Cytokines that are elevated in ICI-induced IA patient sera could serve as future therapeutic targets. Finally, understanding presence of autoantibodies and when they develop in the course of ICI treatment will give insight into pathogenesis and identify potential biomarkers. Concurrently with conducting research during the proposal, the candidate will participate in a variety of career development activities taking advantage of the rich resources of Johns Hopkins in the Division of Rheumatology, the Bloomberg Kimmel Institute for Cancer Immunotherapy, and the Bloomberg School of Public Health. The candidate will participate in didactic coursework, conferences, and mentoring meetings with a diverse group of mentors from rheumatology, oncology, laboratory science, and data science. At the end of this award, the candidate will be an independent clinical investigator in the area of cancer immunotherapy and autoimmune disease and will establish a multi- center consortium with standardized data and biospecimen collection for rheumatic irAEs and for patients with preexisting autoimmune disease who are treated with ICIs.

项目概要/摘要该提案的主要目标是获得成为独立临床和转化人员所需的技能风湿病学研究人员，以增进对新风湿病炎症性关节炎的了解 (IA) 由于免疫检查点抑制剂 (ICIs)。 ICI 正在彻底改变癌症治疗，但也导致免疫相关的不良事件。 ICI 诱发的 IA 是最有可能发生的免疫相关不良事件风湿病专家遇到过。 ICI 诱发的 IA 会导致显着的发病率，并且具有临床异质性，并且 ICI 停止后仍可持续。拟议的项目将利用一组特征明确的 ICI 患者诱导 IA 和 ICI 治疗的未发生 IA 的对照患者解决了几个重要问题。首先，将评估 ICI 诱导的 IA 的临床异质性以及预测 IA 持续性的因素超越 ICI 治疗的停止将被确定。接下来，临床和免疫遗传学危险因素将确定发生 ICI 诱导的 IA。最后，血清细胞因子谱和自身抗体之前和 ICI 治疗后，将比较 ICI 诱导的 IA 患者和接受 ICI 治疗的对照患者 ICI 并不发展 IA。这些实验将解决这一新兴临床的关键知识差距实体。具体来说，定义相关的临床亚组将允许对以下疾病进行差异化监测和治疗：患者。了解 IA 发展的危险因素将有助于在治疗前对患者进行风险分层治疗。 ICI 诱导的 IA 患者血清中升高的细胞因子可以作为未来的治疗靶点。最后，了解自身抗体的存在以及它们在 ICI 治疗过程中何时出现将有助于深入了解发病机制并确定潜在的生物标志物。期间进行研究的同时根据该提案，候选人将利用以下机会参加各种职业发展活动约翰霍普金斯大学风湿病科、彭博金梅尔癌症研究所的丰富资源免疫疗法和彭博公共卫生学院。候选人将参加教学与来自风湿病学的不同导师群体进行课程作业、会议和指导会议，肿瘤学、实验室科学和数据科学。获奖后，候选人将成为独立人士癌症免疫治疗和自身免疫性疾病领域的临床研究者，并将建立一个多中心联盟，为风湿性 irAE 和患有以下疾病的患者提供标准化数据和生物样本收集既往患有自身免疫性疾病并接受 ICI 治疗的人。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Immune checkpoint inhibitor toxicities: systems-based approaches to improve patient care and research.

免疫检查点抑制剂毒性：改善患者护理和研究的基于系统的方法。

DOI：
10.1016/s1470-2045(20)30107-8
发表时间：
2020-08-01
期刊：
The Lancet. Oncology
影响因子：
0
作者：
Douglas B. Johnson;K. Reynolds;R. Sullivan;J. Balko;J. Patrinely;L. Cappelli;J. Naidoo;J. Moslehi
通讯作者：
J. Moslehi

Patients with checkpoint inhibitor-induced inflammatory arthritis do not become seropositive for anti-cyclic citrullinated peptide when followed over time.

随着时间的推移，患有检查点抑制剂诱导的炎症性关节炎的患者不会出现抗环瓜氨酸肽血清阳性。