Targetable Immune Evasion Pathways in Hodgkin Lymphoma
Targetable Immune Evasion Pathways in Hodgkin Lymphoma
批准号:
9176760
负责人:
Margaret A Shipp
金额:
$41.09万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-08-22 至 2021-06-30
关键词:
9p24.1AddressAdultAntigen PresentationAntigen-Presenting CellsAppearanceAutologousB-Cell LymphomasB-LymphocytesBiological MarkersBiopsy SpecimenBlocking AntibodiesCell SurvivalClinicalClinical TrialsClonalityCombined Modality TherapyCustomCytometryDataDevelopmentDiagnosisDiagnosticDiseaseEmployee StrikesEvaluationEventFormalinFrequenciesGeneticHodgkin DiseaseHybridsImmuneImmunotherapyIncidenceLigandsMHC Class I GenesMalignant - descriptorMalignant lymphoid neoplasmMediastinalMetabolismMutationNatural Killer CellsNeoadjuvant TherapyOutcomePDCD1LG1 geneParaffin EmbeddingPathway interactionsPatient AgentsPatientsPeripheral Blood Mononuclear CellPilot ProjectsReceptor SignalingRecurrenceReed-Sternberg CellsRefractoryRegimenRelapseResistanceSeriesSignal TransductionSorting - Cell MovementSpecimenStem cell transplantSuspension substanceSuspensionsT-Cell ProliferationT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsTimeTranslatingbasecell typechemotherapeutic agentdeep sequencingdesignexhaustionexome sequencingexperiencefollow-upgenetic analysisinsightmacrophagemonocyteneoplastic cellprognostic significancereceptorresponsetherapeutic targettooltranscription factortumortumor microenvironment
中文摘要
项目摘要
我们目前的诊断和治疗淋巴系统恶性肿瘤的方法并没有反映新出现的数据
探讨其发病机制和合理的治疗靶点。例如,主要的
淋巴恶性肿瘤袭击年轻人和其他健康成人,经典霍奇金淋巴瘤(cHL),
很大程度上由其形态学外观来定义,并使用现有的经验性组合进行治疗。
化疗剂。我们以前假设9p24.1/PD-L1/PD-L2拷贝数改变
(CNA)是cHL免疫逃避的遗传机制,并认为PD-1通路是一种合理的免疫逃避机制。
治疗的目标。在定义复发性9p24.1拷贝增加和PD-L1/PD-L2增加后
作为cHL中的高频事件,我们探索了PD-1阻断在这种淋巴细胞中的临床活性,
恶性肿瘤在两种不同PD-1阻断剂的独立初步研究中,
复发性/难治性cHL经历了显著的临床反应,通常是持久的。调整竞技
更新申请,我们建议建立在这些调查结果与以下具体目标:1.0)确定
PD-L1/PD-L2改变与结局、对PD-1阻断的应答和其他遗传因素之间的关系
cHL中免疫逃避的基础; 2.0)阐明cHL中对PD-1阻断的应答和抵抗机制,
3.0)开发一种全面的方法来分析cHL中免疫逃避的遗传基础;
和4.0)在治疗cHL的较早时间点定义PD-1阻断的临床活性。的
拟议的研究将确定免疫逃避的互补和/或混杂遗传基础,
对PD-1阻断的应答和抗性机制,并告知我们将PD-1阻断纳入
cHL的标准疗法
英文摘要
Project Summary
Our current approaches to the diagnosis and treatment of lymphoid malignancies do not reflect emerging data
regarding pathogenetic mechanisms and associated rational treatment targets. For example, one of the main
lymphoid malignancies to strike young and otherwise healthy adults, classical Hodgkin lymphoma (cHL), is
largely defined by its morphologic appearance and treated with an empiric combination of available
chemotherapeutic agents. We previously hypothesized that 9p24.1/PD-L1/PD-L2 copy number alteration
(CNA) was a genetic mechanism of immune evasion in cHL and considered the PD-1 pathway to be a rational
therapeutic target in this disease. After defining recurrent 9p24.1 copy gain and increased PD-L1/PD-L2
expression as high-frequency events in cHL, we explored the clinical activity of PD-1 blockade in this lymphoid
malignancy. In independent pilot studies of two different PD-1 blocking agents, patients with multiply
relapsed/refractory cHL experienced remarkable clinical responses that were often durable. In our competitive
renewal application, we propose to build on these findings with the following specific aims: 1.0) Determine the
relationship between PD-L1/PD-L2 alterations and outcome, response to PD-1 blockade and additional genetic
bases of immune evasion in cHL; 2.0) Elucidate mechanisms of response and resistance to PD-1 blockade in
cHL patients; 3.0) Develop a comprehensive approach to analyze genetic bases for immune evasion in cHL;
and 4.0) Define the clinical activity of PD-1 blockade at earlier timepoints in the treatment of cHL. The
proposed studies, will define complementary and/or confounding genetic bases of immune evasion and
mechanisms of response and resistance to PD-1 blockade and inform our incorporation of PD-1 blockade into
the standard therapy of cHL.
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会议论文
Targetable Immune Evasion Pathways in Hodgkin Lymphoma
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批准号:9326921
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项目类别:
-
资助金额:$37.34万
-
财政年份:2011
-
负责人:Margaret A Shipp
-
依托单位:
Complementary Signaling Pathways In Hodgkin Lymphoma and Related Malignancies
-
批准号:8507178
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项目类别:
-
资助金额:$40.23万
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财政年份:2011
-
负责人:Margaret A Shipp
-
依托单位:
Complementary Signaling Pathways In Hodgkin Lymphoma and Related Malignancies
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批准号:8161801
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项目类别:
-
资助金额:$44.97万
-
财政年份:2011
-
负责人:Margaret A Shipp
-
依托单位:
Complementary Signaling Pathways In Hodgkin Lymphoma and Related Malignancies
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批准号:8323281
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项目类别:
-
资助金额:$41.07万
-
财政年份:2011
-
负责人:Margaret A Shipp
-
依托单位:
Complementary Signaling Pathways In Hodgkin Lymphoma and Related Malignancies
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批准号:8895859
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项目类别:
-
资助金额:$42.52万
-
财政年份:2011
-
负责人:Margaret A Shipp
-
依托单位:
Complementary Signaling Pathways In Hodgkin Lymphoma and Related Malignancies
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批准号:8685193
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项目类别:
-
资助金额:$41.38万
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财政年份:2011
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负责人:Margaret A Shipp
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依托单位:
PROGRAM PROJECT GRANT: Molecular Targets of Germinal Center B-Cell Lymphomas
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批准号:7920581
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项目类别:
-
资助金额:$106.18万
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财政年份:2009
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负责人:Margaret A Shipp
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依托单位:
Administrative
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批准号:7158249
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项目类别:
-
资助金额:$9.42万
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财政年份:2006
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负责人:Margaret A Shipp
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依托单位:
Molecular Heterogeneity and Rational Thereapeutic Targets in Large B-Cell Lymphom
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批准号:7158239
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项目类别:
-
资助金额:$28.21万
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财政年份:2006
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负责人:Margaret A Shipp
-
依托单位:
PROGRAM PROJECT GRANT: Molecular Targets of Germinal Center B-Cell Lymphomas
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批准号:7277242
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项目类别:
-
资助金额:$321.42万
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财政年份:2001
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负责人:Margaret A Shipp
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依托单位:
Molecular Targets of Germinal Center B Cell Lymphomas
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批准号:6369196
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项目类别:
-
资助金额:$290.59万
-
财政年份:2001
-
负责人:Margaret A Shipp
-
依托单位:
PROGRAM PROJECT GRANT: Molecular Targets of Germinal Center B-Cell Lymphomas
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批准号:7896696
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项目类别:
-
资助金额:$334.47万
-
财政年份:2001
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负责人:Margaret A Shipp
-
依托单位:
Molecular Targets of Germinal Center B Cell Lymphomas
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批准号:6515221
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项目类别:
-
资助金额:$297.66万
-
财政年份:2001
-
负责人:Margaret A Shipp
-
依托单位:
PROGRAM PROJECT GRANT: Molecular Targets of Germinal Center B-Cell Lymphomas
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批准号:8322972
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项目类别:
-
资助金额:$7.5万
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财政年份:2001
-
负责人:Margaret A Shipp
-
依托单位:
Molecular Targets of Germinal Center B Cell Lymphomas
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批准号:6615514
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项目类别:
-
资助金额:$310.99万
-
财政年份:2001
-
负责人:Margaret A Shipp
-
依托单位:
Molecular Targets of Germinal Center B Cell Lymphomas
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批准号:6918673
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项目类别:
-
资助金额:$328.51万
-
财政年份:2001
-
负责人:Margaret A Shipp
-
依托单位:
PROGRAM PROJECT GRANT: Molecular Targets of Germinal Center B-Cell Lymphomas
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批准号:7472504
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项目类别:
-
资助金额:$323.34万
-
财政年份:2001
-
负责人:Margaret A Shipp
-
依托单位:
Molecular Targets of Germinal Center B Cell Lymphomas
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批准号:6787245
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项目类别:
-
资助金额:$319.73万
-
财政年份:2001
-
负责人:Margaret A Shipp
-
依托单位:
PROGRAM PROJECT GRANT: Molecular Targets of Germinal Center B-Cell Lymphomas
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批准号:7136452
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项目类别:
-
资助金额:$321.94万
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财政年份:2001
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负责人:Margaret A Shipp
-
依托单位:
PROGRAM PROJECT GRANT: Molecular Targets of Germinal Center B-Cell Lymphomas
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批准号:7666787
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项目类别:
-
资助金额:$331.68万
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财政年份:2001
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负责人:Margaret A Shipp
-
依托单位:
海外基金