(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:
  • 金额:
    $ 51.11万
  • 依托单位:
  • 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

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(>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:
  • 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:
  • 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.
  • DOI:
    10.1093/oncolo/oyad184
  • 发表时间:
    2023-09-07
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Approach to the Patient With Immune Checkpoint Inhibitor-Associated Endocrine Dysfunction.
免疫检查点抑制剂相关内分泌功能障碍患者的治疗方法。
Incidence of Cutaneous Immune-Related Adverse Events and Outcomes in Immune Checkpoint Inhibitor-Containing Regimens: A Systematic Review and Meta-Analysis.
  • DOI:
    10.3390/cancers16020340
  • 发表时间:
    2024-01-13
  • 期刊:
  • 影响因子:
    5.2
  • 作者:
    Curkovic, Nina B.;Bai, Kun;Ye, Fei;Johnson, Douglas B.
  • 通讯作者:
    Johnson, Douglas B.
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Justin M Balko其他文献

Justin M Balko的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Justin M Balko', 18)}}的其他基金

Immunologic and Antigenic Drivers of Immune Checkpoint Inhibitor-Associated Myocarditis
免疫检查点抑制剂相关心肌炎的免疫学和抗原驱动因素
  • 批准号:
    10618791
  • 财政年份:
    2021
  • 资助金额:
    $ 51.11万
  • 项目类别:
Immunologic and Antigenic Drivers of Immune Checkpoint Inhibitor-Associated Myocarditis
免疫检查点抑制剂相关心肌炎的免疫学和抗原驱动因素
  • 批准号:
    10386891
  • 财政年份:
    2021
  • 资助金额:
    $ 51.11万
  • 项目类别:
Immunologic and Antigenic Drivers of Immune Checkpoint Inhibitor-Associated Myocarditis
免疫检查点抑制剂相关心肌炎的免疫学和抗原驱动因素
  • 批准号:
    10219907
  • 财政年份:
    2021
  • 资助金额:
    $ 51.11万
  • 项目类别:
(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
  • 批准号:
    9891975
  • 财政年份:
    2019
  • 资助金额:
    $ 51.11万
  • 项目类别:
(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
  • 批准号:
    10133451
  • 财政年份:
    2019
  • 资助金额:
    $ 51.11万
  • 项目类别:
(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
  • 批准号:
    10359717
  • 财政年份:
    2019
  • 资助金额:
    $ 51.11万
  • 项目类别:
Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies
Dusp4 在乳腺癌中的作用:肿瘤抑制生物学和治疗策略
  • 批准号:
    8765222
  • 财政年份:
    2014
  • 资助金额:
    $ 51.11万
  • 项目类别:
Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies
Dusp4 在乳腺癌中的作用:肿瘤抑制生物学和治疗策略
  • 批准号:
    9044055
  • 财政年份:
    2014
  • 资助金额:
    $ 51.11万
  • 项目类别:
Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies
Dusp4 在乳腺癌中的作用:肿瘤抑制生物学和治疗策略
  • 批准号:
    9268419
  • 财政年份:
    2014
  • 资助金额:
    $ 51.11万
  • 项目类别:
Dusp4 in breast cancer: tumor suppressor biology and therapeutic strategies
Dusp4 在乳腺癌中的作用:肿瘤抑制生物学和治疗策略
  • 批准号:
    9061648
  • 财政年份:
    2014
  • 资助金额:
    $ 51.11万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 51.11万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 51.11万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 51.11万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 51.11万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 51.11万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 51.11万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 51.11万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 51.11万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 51.11万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 51.11万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了