Escape from CAR T surveillance through lineage plasticity
通过谱系可塑性逃避 CAR T 监控
基本信息
- 批准号:10419173
- 负责人:
- 金额:$ 57.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive Cell TransfersAdultAffectAntigensB lymphoid malignancyB-Cell Acute Lymphoblastic LeukemiaB-LymphocytesB-cell precursor acute lymphoblastic leukemia cellBiological ModelsBiologyBlocking AntibodiesBone MarrowCD19 AntigensCD19 geneCRISPR/Cas technologyCancer ModelCell CommunicationCell LineCell TherapyCellsCharacteristicsChildhoodChildhood Precursor B Lymphoblastic LeukemiaCoupledCytokine SignalingDataDevelopmentDisease remissionEffectivenessEnvironmentEpigenetic ProcessEpithelialEvolutionExhibitsFrequenciesGene Expression ProfileGeneticGenomicsHematologic NeoplasmsHematopoiesisHeterogeneityImmuneImmune checkpoint inhibitorImmunologicsImmunotherapeutic agentImmunotherapyInfantInflammatoryInterleukin-1Interleukin-6InterventionIntrinsic factorKnockout MiceLeadLymphomaMLL geneMLL-rearranged leukemiaMalignant NeoplasmsMethodsModelingMouse StrainsMultiple MyelomaMyelogenousNewborn InfantPathogenesisPatientsPatternPhenotypeProductionProtocols documentationRefractoryRelapseResistanceRoleSignal PathwaySignal TransductionSiteSolid NeoplasmStudy modelsSurface AntigensSystemT-LymphocyteTCF3 geneTestingTherapeuticbcr-abl Fusion Proteinscancer cellcancer therapychimeric antigen receptorcurative treatmentscytokinecytotoxicdesigngenetically modified cellsimmune checkpoint blockadeimprovedin vivoinnovationleukemiamolecular targeted therapiesmouse modelnovelnovel strategiesphenotypic biomarkerpressurepreventrelapse patientsresponsetherapeutic targettransplant modeltumor
项目摘要
PROJECT SUMMARY
Cancer cell genomic plasticity can enable resistance to cancer therapy for both solid tumors and
hematologic malignancy. Escape from cytotoxic or molecularly targeted therapy through an
inherent capacity to reprogram differentiation state or lineage has now been described following
adoptive cell therapy or immune checkpoint blockade in adult epithelial tumors. Transfer of T
cells genetically modified to express chimeric antigen receptors (CAR T cells) targeting the B
cell surface antigen CD19 induces remission in 70-90% of patients with relapsed/refractory B
cell acute lymphocytic leukemia (B-ALL) resulting in FDA-approval for this indication. However,
a large fraction of those patients relapse within one year of treatment. This occurs with two main
patterns, 1) early antigen-positive (CD19pos) relapse, attributed to poor CAR T expansion or lack
of persistence, and 2) later antigen-negative relapse. Evasion of CD19-targeted immunotherapy
can result from loss of all B lineage phenotypic markers with acquisition of stable, alternative
phenotypes in MLL-rearranged (MLL-r), BCR-ABL driven, TCF3-ZNF384 and other subtypes of
ALL. Remarkably, emergence of phenotypic switch can occur years after CD19-targeted
immunotherapy. Understanding the mechanisms of immunotherapeutic resistance and
identifying strategies to overcome these will be critical in improving remission depth and
durability of response.
Our proposal will address two major deficits in cancer models to identify factors
contributing to relapse from immunotherapy: the lack of immune-intact model systems that
recapitulate the lineage switching phenomenon observed using CD19-targeted immunotherapy
and the lack of faithful mouse models recapitulating infant/childhood MLL-r B-ALL. This
collaborative proposal brings together the extensive expertise of the Ernst group in the biology
of MLL-r leukemia and hematopoiesis with the CAR T cell expertise of the Fry/Kohler groups to
develop innovative new models systems to study evasion from CAR T cell therapy through
lineage reprogramming. Our preliminary CAR T cell data employs immune-intact mouse models
to illustrate that CD19neg relapse includes cells that exhibit gain of myeloid antigens and a
myeloid transcriptional profile. On the pediatric B-ALL front, we develop a retroviral system to
produce B-ALL that captures the inherent plasticity of MLL-r leukemias and switches to AML in
vivo. Our proposal assesses the ability for both leukemia-intrinsic as well as extrinsic host-
environmental components to influence escape from CAR T killing through lineage
reprogramming. The findings of our studies, including the discovery of novel strategies to block
lineage reprogramming have the potential to inform the development of similar approaches in
other forms of cancer treated with cellular therapy and, potentially, immune checkpoint
inhibitors. In addition, these studies may lead to a better understanding of lineage plasticity and
the extent to which epigenetic heterogeneity contributes to relapse, which can directly inform the
design of curative therapies.
项目总结
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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Patricia Ernst其他文献
Patricia Ernst的其他文献
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{{ truncateString('Patricia Ernst', 18)}}的其他基金
Escape from CAR T surveillance through lineage plasticity
通过谱系可塑性逃避 CAR T 监控
- 批准号:
10581656 - 财政年份:2022
- 资助金额:
$ 57.87万 - 项目类别:
Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model
通过调节组蛋白甲基转移酶增强造血功能:评估新的 MLL1 功能获得动物模型
- 批准号:
9814577 - 财政年份:2019
- 资助金额:
$ 57.87万 - 项目类别:
Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model
通过调节组蛋白甲基转移酶增强造血功能:评估新的 MLL1 功能获得动物模型
- 批准号:
10212374 - 财政年份:2019
- 资助金额:
$ 57.87万 - 项目类别:
Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model
通过调节组蛋白甲基转移酶增强造血功能:评估新的 MLL1 功能获得动物模型
- 批准号:
10017193 - 财政年份:2019
- 资助金额:
$ 57.87万 - 项目类别:
MLL Family Histone Methyltransferases in Myeloid Leukemia
髓系白血病中的 MLL 家族组蛋白甲基转移酶
- 批准号:
10406930 - 财政年份:2018
- 资助金额:
$ 57.87万 - 项目类别:
Modeling hematologic malignancy and self-renewal with gain-of-function MLL1
利用功能获得 MLL1 模拟血液恶性肿瘤和自我更新
- 批准号:
8974958 - 财政年份:2014
- 资助金额:
$ 57.87万 - 项目类别:
MLL Function in the Maintenance of the Blood Forming System
MLL 在维持造血系统中的功能
- 批准号:
8974685 - 财政年份:2014
- 资助金额:
$ 57.87万 - 项目类别:
MLL Function in the Maintenance of the Blood Forming System
MLL 在维持造血系统中的功能
- 批准号:
7867478 - 财政年份:2009
- 资助金额:
$ 57.87万 - 项目类别:
ROLE OF THE CHROMATIN REGULATOR, MLL, IN T CELL DEVELOPMENT
染色质调节因子 MLL 在 T 细胞发育中的作用
- 批准号:
7959994 - 财政年份:2009
- 资助金额:
$ 57.87万 - 项目类别:
ROLE OF THE CHROMATIN REGULATOR, MLL, IN T CELL DEVELOPMENT
染色质调节因子 MLL 在 T 细胞发育中的作用
- 批准号:
7720751 - 财政年份:2008
- 资助金额:
$ 57.87万 - 项目类别:














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