(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/摘要在此提案中，我们将确定临床转换的预测性和早期响应生物标志物的发展癌症患者中由免疫检查点抑制剂（ICI）治疗引起的免疫相关不良事件（IRAE）。使用我们将采用集中和公正的筛选方法，我们将利用一个大型的机构间和多学科团队研究人员以及大型（> 350名患者）回顾性和前瞻性组织和外周血 ICI治疗的患者的标本库，其中许多患者出现了严重的伊拉斯。使用此组织库以及其他标本前瞻性地在我们的机构收集并通过合作机构，我们将确定在患有严重IRAE的HLA匹配患者中扩展或上调的TCR和自身抗体。使用宽网络技术（全蛋白肽微阵列，10亿酵母PMHC展示库，数字空间分析），我们将在ICI治疗之前和之后鉴定外周血和组织中的致病性T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和T细胞室的细胞将在患有IRAE和临床/HLA匹配对照的患者中进行。调查结果将被比较治疗结果（临床反应和特定器官的伊拉斯），我们将测试这些生物标志物是否可以是在ICI治疗开始之前检测到。可翻译的自身抗体生物标志物将通过新颖的护理来验证临床实用程序的自定义阵列技术。最后，我们将在匹配的肿瘤和IRAE部位中介绍TCR曲目使用T细胞的单细胞RNA测序的样品，与高度新颖的〜1结合抗原鉴定十亿酵母PMHC展示文库的方法，以识别IRAE背后的致病机制。使用这些数据，我们将在此提案中解决三个具体目标：1）我们将前瞻性地表征治疗伊拉斯的细胞介导的机制； 2）我们将确定与IRAE相关的自身抗体或TCR是否可以是在使用ICIS治疗之前确定； 3）我们将确定致病性TCR的抗原靶标，并配置它们跨肿瘤和患病组织的表达。由于ICIS取得了巨大的成功，这些治疗将用于越来越多的患者，并转移到较早的治疗线。因此，有伊拉斯风险的患者人数将继续增加。该建议将解决越来越需要如何识别和管理有ICIS严重不良后遗症的患者，同时确定伊拉斯病原机制的新发现。

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.