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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.

项目总结/摘要在这项提案中，我们将确定临床上可翻译的预测和早期反应生物标志物，用于开发癌症患者中免疫检查点抑制剂（ICI）治疗引起的免疫相关不良事件（irAE）。使用我们将利用一个大型的跨机构和多学科的团队，的研究者，以及大量（>350例患者）回顾性和前瞻性生长组织和外周血 ICI治疗患者的样本库，其中许多患者发生了重度irAE。利用这个组织库，在我们的机构和通过合作机构预期收集的其他标本，我们将确定在发生重度irAE的HLA匹配患者中扩增或上调的TCR和自身抗体。使用广域网技术（全蛋白质组肽微阵列，10亿酵母pMHC展示文库，数字空间分析），我们将鉴定ICI治疗前后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以及T细胞区室的CyTOF 将在发生irAE的患者和临床/HLA匹配的对照中进行。将结果与治疗结果（临床反应和器官特异性irAE），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志物将通过一种新的床旁检测方法进行验证用于临床应用的定制阵列技术。最后，我们将在匹配的肿瘤和irAE位点中分析TCR库。标本使用T细胞的单细胞RNA测序，再加上抗原鉴定通过一个高度新颖的~1 10亿酵母pMHC展示文库方法来鉴定irAE背后的致病机制。利用这些数据，我们将在本提案中解决三个具体目标：1）我们将前瞻性地描述治疗中的 irAE的细胞介导机制; 2）我们将确定irAE相关的自身抗体或TCR是否可以我们将在用ICI治疗之前鉴定抗原靶点;以及3）我们将鉴定致病性TCR的抗原靶点，并对其进行分析。在肿瘤和患病组织中的表达。由于ICIs的巨大成功，这些治疗将用于越来越多的患者，并转移到早期的治疗方法因此，存在irAE风险的患者数量将继续增加;本提案将解决如何识别和管理面临ICI严重不良后遗症风险的患者的需求日益未得到满足，确定irAE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.