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
基本信息
- 批准号:10219907
- 负责人:
- 金额:$ 83.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAdoptive TransferAffectAftercareAntigen TargetingAntigensArrhythmiaAttenuatedAutoimmuneAutoimmunityAutomobile DrivingBenefits and RisksBiologicalBiological MarkersBlocking AntibodiesCD8-Positive T-LymphocytesCD8B1 geneCTLA4 geneCardiacCardiologyCardiovascular DiseasesCardiovascular systemCell LineCellsCessation of lifeClinicalComplicationDataDeath RateDevelopmentEtiologyEventFatality rateFunctional disorderGenesGeneticGrantHeartHumanImmuneImmune TargetingImmune checkpoint inhibitorImmune systemImmunologicsImmunologistImmunologyImmunotherapyInfiltrationInflammatoryInternationalInterruptionLeadLigandsMalignant NeoplasmsModelingMonoclonal AntibodiesMusMuscleMuscle CellsMyelogenousMyocardialMyocarditisMyocardiumMyositisOncologistOncologyPDL1 pathwayPathogenesisPathogenicityPathologicPathologyPatientsPhenocopyPhenotypePlayPopulationPre-Clinical ModelPrevention strategyReceptor ActivationRisk ManagementRoleSamplingScientistSelf ToleranceSkeletal MuscleSpecimenStriated MusclesStructureT-Cell ActivationT-Cell DevelopmentT-Cell ReceptorT-LymphocyteTestingTherapeuticThymus GlandTissue BanksToxic effectTranscriptTranslatingTumor-infiltrating immune cellsWild Type Mousebody systemcancer immunotherapycancer therapycancer typecheckpoint therapycytotoxic CD8 T cellsearly onseteffective therapyexperienceexperimental studyheart damagehuman tissueimmune-related adverse eventsimprovedinsightmacrophagemouse modelnew technologyperipheral tolerancepre-clinicalprogrammed cell death ligand 1programmed cell death protein 1receptorreconstitutionresponsescreeningside effectsingle cell technologysingle-cell RNA sequencingsuccesssystemic autoimmunitytreatment strategy
项目摘要
Project Summary/Abstract
This proposal brings together Dr. Javid Moslehi, a cardio-oncologist and myocyte biologist, and Dr. Justin Balko,
a cancer biologist and immunologist, to define the immunologic and antigenic drivers of myocarditis associated
with cancer immunotherapies. Specifically, immune checkpoint inhibitors (ICI), which block the activity of immune
‘brakes’, such as CTLA-4 or PD-1, have revolutionized treatment for many cancer types but by activating the
immune system, they can lead to autoimmune phenomena, called immune-related adverse events. Our group
has defined the clinical features of ICI-associated myocarditis, characterized by T cell and macrophage infiltration
into the myocardium, fulminant arrhythmias, concurrent myositis, and high fatality rate. To study this entity in
more depth, we have generated pre-clinical mouse models that recapitulate ICI-associated myocarditis:
specifically, a genetic mouse model, where the genes for PD-1 (Pdcd1) and CTLA-4 (Ctla4) are deleted, leads
to early death due to myocarditis which recapitulates human ICI-myocarditis clinically and pathologically.
Surprisingly, the mice do not have systemic autoimmunity; rather the T cell infiltration is limited to the
cardiovascular system and specifically the heart. Similarly, the infiltration seen in patients is often limited to T
cell and macrophage infiltration into striated muscle, namely the heart and skeletal muscle. In this grant, we
hypothesize that specific CD8+ T cell infiltrates restricted to one or more myocardial antigens are the drivers of
pathogenesis in ICI-myocarditis. We seek to define the T cells responsible for the etiology and pathogenesis of
ICI-myocarditis and to demonstrate that specific T cell populations are both necessary and sufficient to drive
pathogenesis (Aim 1). Additionally, we seek to define the antigen targets of ICI-myocarditis in mice and in
patients (Aim 2). We leverage a team of experts in cardiology, oncology and immunology to test our hypothesis
through conduction of these studies. In addition, we have leveraged a large international network of collaborators
to collect cases of ICI-associated myocarditis.
The overwhelming success of ICI is hampered in some patients by the development of fulminant toxicities,
including ICI-myocarditis. This proposal will allow us to generate insights into the mechanisms of this entity,
which we feel can translate into more effective treatment and prevention strategies. In addition, the unique team
of clinicians and scientists we have assembled for this proposal allows incorporation of new technology which
will allow better interrogation of the interactions between the cardiovascular and immune systems translating into
better insights in other forms of inflammatory cardiovascular diseases.
项目摘要/摘要
这项提议汇集了心脏肿瘤学家和心肌细胞生物学家贾维德·莫斯利希博士和贾斯汀·巴尔科博士,
癌症生物学家和免疫学家,以确定与心肌炎相关的免疫和抗原驱动因素
癌症免疫疗法。具体地说,免疫检查点抑制物(ICI),它阻止免疫活性
“刹车”,如CTLA-4或PD-1,已经为许多癌症类型的治疗带来了革命性的变化,但通过激活
免疫系统中,它们会导致自身免疫现象,称为免疫相关不良事件。我们的团队
明确了ICI相关性心肌炎的临床特征,以T细胞和巨噬细胞浸润为特征
进入心肌,暴发性心律失常,并发肌炎,病死率高。要研究此实体,请参阅
更深入地说,我们已经建立了临床前小鼠模型,概括了ICI相关性心肌炎:
具体地说,PD-1(Pdcd1)和CTLA-4(CTLA4)基因缺失的遗传小鼠模型导致
由于心肌炎导致的早期死亡,从临床和病理上概括了人类ICI-心肌炎。
令人惊讶的是,小鼠没有全身性自身免疫;相反,T细胞的渗透仅限于
心血管系统,特别是心脏。同样,患者的浸润通常仅限于T细胞。
细胞和巨噬细胞渗入横纹肌,即心肌和骨骼肌。在这笔赠款中,我们
假设特定的CD8+T细胞仅限于一种或多种心肌抗原的渗入是驱动因素
脑梗塞-心肌炎的发病机制。我们试图定义T细胞负责的病因和发病机制。
ICI心肌炎,并证明特定的T细胞群是必要的和足够的驱动
发病机制(目标1)。此外,我们还试图确定ICI心肌炎的抗原靶点。
患者(目标2)。我们利用心脏病学、肿瘤学和免疫学方面的专家团队来检验我们的假设
通过进行这些研究。此外,我们还利用了一个庞大的国际合作者网络
收集ICI相关性心肌炎病例。
ICI的压倒性成功在一些患者中受到暴发性毒性发展的阻碍,
包括ICI-心肌炎。这项提议将使我们能够深入了解这个实体的机制,
我们认为这可以转化为更有效的治疗和预防战略。此外,独一无二的团队
我们为这项提案召集的临床医生和科学家允许纳入新技术,
将允许更好地询问心血管系统和免疫系统之间的相互作用,转化为
对其他形式的炎症性心血管疾病有更好的见解。
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:
$ 83.21万 - 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:
$ 83.21万 - 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:
$ 83.21万 - 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:
$ 83.21万 - 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:
$ 83.21万 - 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:
$ 83.21万 - 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:
$ 83.21万 - 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:
$ 83.21万 - 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:
$ 83.21万 - 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:
$ 83.21万 - 项目类别:
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