Aak1 to increase infiltration of adoptively transferred cells into solid tumors
Aak1 增加过继转移细胞向实体瘤的浸润
基本信息
- 批准号:10558244
- 负责人:
- 金额:$ 45.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-02-16 至 2028-01-31
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinAdoptive Cell TransfersAdoptive TransferB lymphoid malignancyBindingBiochemicalCXC chemokine receptor 3CXCL10 geneCXCR3 geneCell Signaling ProcessCell surfaceCellsChemotaxisClathrinClinicalDataDevelopmentDominant-Negative MutationEndocytic VesicleEndocytosisEngineeringEvaluationFlow CytometryGene MutationGenesGeneticGenetic ScreeningGoalsHela CellsHumanImageIn VitroIndividualInfiltrationKnock-outKnockout MiceLigandsMalignant NeoplasmsMeasuresMediatingMicroscopyModelingModificationMolecularMusMutateMutationPhosphotransferasesPlayProcessProteinsReceptor SignalingRegulationRegulatory PathwayReportingRoleSeriesSleeping BeautySolid NeoplasmSurfaceSystemT cell infiltrationT cell therapyT-LymphocyteTestingTherapeuticTissuesTreatment EfficacyXenograft procedurecancer immunotherapycell motilitychemokinechemokine receptorchimeric antigen receptorchimeric antigen receptor T cellscytotoxicdesignenhancer-binding protein AP-2experimental studygenome wide screenimmune checkpointimprovedin vivoinnovationmelanomamigrationmutantnew therapeutic targetnoveloverexpressionpharmacologicpre-clinicalreceptorreceptor expressionstandard caresuccesstargeted treatmenttherapeutic targettraffickingtranslational potentialtreatment strategytumortumor growthtumor microenvironment
项目摘要
PROJECT SUMMARY/ABSTRACT
Insufficient T cell infiltration is a major challenge in adoptive transfer therapies like CAR-T. Therefore, one
strategy to improve therapy is to enhance T cell trafficking into tumors. However, current therapies targeting T
cell activities largely consist of immune checkpoint modulators, and very little innovation has occurred in
therapeutic design targeting T cell intrinsic regulators of intratumoral accumulation. This is due, in part, to an
incomplete understanding of the regulatory pathways involved in T cell trafficking. We recently identified Adapter
protein 2 associated kinase 1 (Aak1) as an important regulator of T cell chemotaxis into tumors in an in vivo
forward genetic screen. The primary objective of this project is to measure the translational potential of AAK1 as
a therapeutic target in cancer to augment adoptive transfer therapies, with the additional goal of better
understanding molecular functions of Aak1 as a regulator of chemokine receptor Cxcr3 internalization. These
goals will be accomplished in three aims. Aim 1 will quantify the impact of genetic modification of Aak1 on tumor
infiltration of adoptively transferred T cells in a preclinical solid tumor model. Aim 2 will determine whether Aak1
kinase activity is required for chemokine-induced internalization of Cxcr3 in primary T cells. Aim 3 will measure
the degree to which Aak1 modification impacts therapeutic efficacy in adoptive transfer therapies. This proposal
has several innovative aspects, including characterization of a novel, T cell specific Aak1 knockout mouse,
functional and mechanistic testing of a novel Aak1 mutant construct, and evaluation of Aak1 as a novel
therapeutic target to limit T cell chemotaxis into inflamed tissue. Successful completion of this project will benefit
development of novel treatment strategies for solid tumors, and findings can broadly be applied to any T cell
adoptive transfer approach and is not limited to individual CAR or TCR engineered platforms.
项目总结/摘要
T细胞浸润不足是CAR-T等过继转移疗法的主要挑战。因此,一
改善治疗的策略是增强T细胞向肿瘤中的运输。然而,目前针对T
细胞活动主要由免疫检查点调节剂组成,而且几乎没有创新
靶向肿瘤内积累的T细胞内在调节因子的治疗设计。这在一定程度上是由于
对参与T细胞运输的调节途径的不完全理解。我们最近发现适配器
蛋白2相关激酶1(Aak 1)作为体内T细胞趋化性进入肿瘤的重要调节因子,
遗传筛查该项目的主要目的是测量AAK 1的翻译潜力,
癌症的治疗靶点,以增强过继转移治疗,其额外目标是更好地
了解Aak 1作为趋化因子受体Cxcr 3内化调节剂的分子功能。这些
目标将在三个方面实现。目的1:量化Aak 1基因修饰对肿瘤的影响
在临床前实体瘤模型中过继转移的T细胞的浸润。目标2将决定Aak 1是否
激酶活性是趋化因子诱导的Cxcr 3在原代T细胞中内化所必需的。目标3将衡量
Aak 1修饰在何种程度上影响过继转移治疗的疗效。这项建议
具有几个创新方面,包括表征一种新的T细胞特异性Aak 1敲除小鼠,
新的Aak 1突变体构建体的功能和机制测试,以及Aak 1作为新的
治疗靶点,以限制T细胞趋化性进入发炎组织。该项目的成功完成将使
开发新的实体瘤治疗策略,研究结果可广泛应用于任何T细胞
本发明的CAR或TCR工程化平台可以是过继转移方法,并且不限于单独的CAR或TCR工程化平台。
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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Laura Marie Rogers其他文献
Laura Marie Rogers的其他文献
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{{ truncateString('Laura Marie Rogers', 18)}}的其他基金
Understanding the impact of AAK1 on T cell chemokine receptor expression and chemotaxis
了解 AAK1 对 T 细胞趋化因子受体表达和趋化性的影响
- 批准号:
10300774 - 财政年份:2021
- 资助金额:
$ 45.76万 - 项目类别:
Rationally improving T cell-mediated immunotherapy using Sleeping Beauty mutagenesis
利用睡美人诱变合理改进 T 细胞介导的免疫治疗
- 批准号:
10238780 - 财政年份:2019
- 资助金额:
$ 45.76万 - 项目类别:
Rationally improving T cell-mediated immunotherapy using Sleeping Beauty mutagenesis
利用睡美人诱变合理改进 T 细胞介导的免疫治疗
- 批准号:
9503289 - 财政年份:2019
- 资助金额:
$ 45.76万 - 项目类别: