(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:10359717
- 负责人:
- 金额:$ 50.71万
- 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 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse reactionsAffectAntigen TargetingAntigensAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmunityAutopsyB-LymphocytesBiological MarkersBiological Specimen BanksBiopsyCTLA4 geneCancer PatientCell CompartmentationCellsClinicalClonal ExpansionClone CellsColitisCoupledCustomDataDevelopmentDiseaseEncephalitisEtiologyFrequenciesGeneticImmune checkpoint inhibitorImmunotherapyIncidenceInstitutionLibrariesLongitudinal StudiesLymphocyteMalignant NeoplasmsMediatingMetastatic MelanomaMethodsMuscleMyocarditisMyocardiumMyositisNatureNivolumabNormal tissue morphologyOrganOutcomePD-1/PD-L1PathogenicityPathologyPatientsPeptide/MHC ComplexPeptidesPeripheralProspective StudiesProteomeRNARefractoryReportingResearch PersonnelRiskRisk FactorsRisk ManagementRoleSamplingSelf ToleranceSiteSkeletal Muscle NeoplasmSpecimenT cell clonalityT cell receptor repertoire sequencingT-Cell ActivationT-Cell ReceptorT-LymphocyteT-Lymphocyte EpitopesT-cell receptor repertoireTechnologyTestingTherapeutic UsesTimeTissue BanksTissuesTranscriptTranslatingTreatment outcomeTumor MarkersTumor TissueValidationYeastsanti-tumor immune responseautoimmune toxicityautoreactivitybiomarker developmentcancer therapycase controlcheckpoint inhibitioncheckpoint therapyclinical biomarkersclinically translatabledigitalexhaustionexperienceimmune checkpoint blockadeimmune-related adverse eventsinsightinter-institutionalipilimumabmultidisciplinarynovelnovel therapeuticsperipheral bloodpoint of carepredictive markerpreventprospectiveprotein aminoacid sequencereconstitutionrepositoryresponseresponse biomarkerscreeningsensorsingle-cell RNA sequencingsuccesstranscriptometranscriptomicstumor
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和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。调查结果将与
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(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Justin M Balko其他文献
Justin M Balko的其他文献
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{{ 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:
$ 50.71万 - 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:
$ 50.71万 - 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:
$ 50.71万 - 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:
$ 50.71万 - 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:
10590676 - 财政年份:2019
- 资助金额:
$ 50.71万 - 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:
$ 50.71万 - 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:
$ 50.71万 - 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:
$ 50.71万 - 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:
$ 50.71万 - 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:
$ 50.71万 - 项目类别:
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