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(PQ8) Patient- and tumor-specific biomarkers and mechanisms that predict irAEs resulting from checkpoint inhibition

(PQ8) 患者和肿瘤特异性生物标志物和预测检查点抑制引起的 irAE 的机制

基本信息

批准号：
10590676
负责人：
Justin M Balko
金额：
$ 51.11万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10590676
关键词：
Adverse reactions Affect Antigen Targeting Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity Autopsy B-Lymphocytes Biological Markers Biological Specimen Banks Biopsy CTLA4 gene Cancer Patient Cell Compartmentation Cells Clinical Clonal Expansion Clone Cells Colitis Collaborations Coupled Custom Data Development Disease Encephalitis Etiology Frequencies Genetic Immune checkpoint inhibitor Immunotherapy Incidence Institution Libraries Longitudinal Studies Lymphocyte Malignant Neoplasms Mediating Metastatic Melanoma Methods Muscle Myocarditis Myocardium Myositis Nature Nivolumab Normal tissue morphology Organ Outcome PD-1/PD-L1 Pathogenicity Pathology Patients Peptide/MHC Complex Peptides Peripheral Prospective Studies Proteome RNA Refractory Reporting Research Personnel Risk Risk Factors Risk Management Role Sampling Self Tolerance Site Skeletal Muscle Specimen T cell clonality T cell receptor repertoire sequencing T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes T-cell receptor repertoire Technology Testing Therapeutic Uses Time Tissue Banks Tissues Transcript Translating Treatment outcome Tumor Markers Tumor Tissue Validation Yeasts anti-tumor immune response autoimmune toxicity autoreactivity biomarker development cancer therapy case control checkpoint inhibition checkpoint therapy clinical biomarkers clinical translation digital exhaustion experience immune checkpoint blockade immune-related adverse events insight inter-institutional ipilimumab multidisciplinary novel novel therapeutics peripheral blood point of care predictive marker prevent prospective protein aminoacid sequence reconstitution repository response response biomarker risk mitigation screening sensor single-cell RNA sequencing success transcriptome transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY/ABSTRACT In this proposal, we will identify clinically-translatable predictive and early-response biomarkers for the development of immune-related adverse events (irAEs) caused by immune checkpoint inhibitor (ICI) therapy in cancer patients. Using both focused and unbiased screening approaches, we will leverage a large inter-institutional and multi-disciplinary team of investigators, as well as a large (>350 patients) retrospective and prospectively growing tissue and peripheral blood bank of specimens from ICI treated patients, many of whom developed severe irAEs. Using this tissue bank, as well as additional specimens prospectively collected at our institution and through collaborating institutions, we will identify TCRs and autoantibodies that are expanded or upregulated in HLA-matched patients experiencing severe irAEs. Using wide-net technologies (whole-proteome peptide microarray, 1 billion yeast pMHC display libraries, digital spatial profiling), we will identify pathogenic T and B cell antigens in peripheral blood and tissue before and after ICI therapy. In longitudinal studies, changes in TCR clonality, changes in autoantibody screening, and CyTOF for T cell compartments will be performed in patients experiencing irAE and in clinically/HLA-matched controls. Findings will be compared to treatment outcomes (clinical response and organ-specific irAEs) and we will test whether these biomarkers can be detected prior to ICI therapy initiation. Translatable autoantibody biomarkers will be validated with a novel point-of-care custom array technology for clinical utility. Finally we will profile the TCR repertoire in matched tumor and site-of-irAE specimens using single-cell RNA sequencing of T cells, coupled with antigen identification through a highly novel ~1 billion yeast pMHC display library approach to identify the pathogenic mechanism behind irAEs. Using these data, we will address three specific aims in this proposal: 1) we will prospectively characterize on-treatment cell-mediated mechanisms of irAEs; 2) we will determine whether irAE-associated autoantibodies or TCRs can be identified prior to treatment with ICIs; and 3) we will identify the antigen targets of pathogenic TCRs and profile their expression across tumor and diseased tissue. Due to the overwhelming success of ICIs, these treatments will be used in increasing numbers of patients and moved to earlier lines of therapy. Thus, the numbers of patients at risk for irAEs will continue to rise; this proposal will address the growing unmet need of how to identify and manage patients at risk for severe adverse sequelae from ICIs, while making new discoveries that identify the pathogenic mechanism of irAEs.

项目摘要/摘要在这项提案中，我们将确定临床可翻译的预测性和早期反应的生物标记物，用于开发免疫检查点抑制剂(ICI)治疗癌症患者引起的免疫相关不良事件(IrAEs)vbl.使用无论是有重点的还是不偏不倚的筛选方法，我们都将利用一个庞大的跨机构和多学科团队研究人员，以及一大群(&gt；350名患者)回顾和预期生长的组织和外周血液来自ICI患者的标本库，其中许多人发展为严重的irAEs。使用这个组织库，以及预期在我们机构和通过合作机构收集的其他标本，我们将确定在经历严重irAEs的HLA相合患者中，TCR和自身抗体被扩大或上调。vbl.使用广网技术(全蛋白质组肽微阵列、10亿酵母pMHC展示文库、数字空间我们将鉴定ICI治疗前后外周血和组织中的致病T细胞和B细胞抗原。在纵向研究中，TCR克隆性的变化，自身抗体筛查的变化，以及T细胞亚群的细胞周期变化将在经历IRAE的患者和临床/人类白细胞抗原匹配的对照中进行。调查结果将与治疗结果(临床反应和器官特异性irAEs)，我们将测试这些生物标志物是否可以在ICI治疗开始前检测到。可翻译的自身抗体生物标记物将通过一种新的护理点进行验证临床应用的定制阵列技术。最后，我们将描述匹配的肿瘤和IRAE部位的TCR谱系标本使用单细胞RNA对T细胞进行测序，结合抗原鉴定通过一种非常新颖的~1 亿酵母pMHC展示文库方法用于鉴定irAEs的致病机制。利用这些数据，我们将解决本提案中的三个具体目标：1)我们将前瞻性地描述正在进行的治疗细胞介导的irAEs机制；2)我们将确定IRAE相关自身抗体或TCRs是否可以在ICIS治疗前识别；3)我们将识别致病TCR的抗原靶标并分析其在肿瘤和病变组织中的表达。由于ICIS的巨大成功，这些治疗方法将在越来越多的患者中使用，并转移到更早的治疗路线。因此，面临irAEs风险的患者数量将继续上升；这项提议将解决日益增长的未得到满足的需求，即如何识别和管理面临ICIS严重不良后遗症风险的患者，同时确定irAEs致病机制的新发现。

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）

A Multicenter Analysis of Immune Checkpoint Inhibitors as Adjuvant Therapy Following Treatment of Isolated Brain Metastasis.

免疫检查点抑制剂作为孤立性脑转移治疗后辅助治疗的多中心分析。

DOI：
10.1002/onco.13608
发表时间：
2021
期刊：
The oncologist
影响因子：
0
作者：
RandallPatrinelyJr.,,J;Funck-Brentano,Elisa;Nguyen,Khang;Rapisuwon,Suthee;Salem,Joe-Elie;Gibney,GeoffreyT;Carlino,Matteo;Johnson,DouglasB
通讯作者：
Johnson,DouglasB

Immune checkpoint inhibitors in patients with pre-existing psoriasis: safety and efficacy.

DOI：
10.1136/jitc-2021-003066
发表时间：
2021-10
期刊：
Journal for immunotherapy of cancer
影响因子：
10.9
作者：
Halle BR;Betof Warner A;Zaman FY;Haydon A;Bhave P;Dewan AK;Ye F;Irlmeier R;Mehta P;Kurtansky NR;Lacouture ME;Hassel JC;Choi JS;Sosman JA;Chandra S;Otto TS;Sullivan R;Mooradian MJ;Chen ST;Dimitriou F;Long G;Carlino M;Menzies A;Johnson DB;Rotemberg VM
通讯作者：
Rotemberg VM

Therapeutic Responses to Combination Nivolumab and Temozolomide as Salvage Therapy for Metastatic Melanoma: A Case Series.