Optimizing CAR T therapy via metabolic engineering for thetreatment of GBM
通过代谢工程优化 CAR T 疗法治疗 GBM
基本信息
- 批准号:10722922
- 负责人:
- 金额:$ 17.82万
- 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:2023-07-05 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:Adoptive TransferAdultAnimalsBioenergeticsBrain NeoplasmsCAR T cell therapyCell LineCellsCellular Metabolic ProcessCentral Nervous SystemCharacteristicsChildClinicalClinical TrialsConsumptionDiseaseEngineeringEnvironmentEvaluationGLUT-3 proteinGlioblastomaGliomaGlucoseGlucose TransporterGlycolysisGoalsHumanImmuneImmune EvasionImmune System DiseasesImmune responseImmune systemImmunotherapeutic agentImmunotherapyInfiltrationLaboratoriesLinkMalignant NeoplasmsMalignant neoplasm of brainMetabolicMetabolic PathwayMetabolismMethodsModelingMutant Strains MiceNF1 geneNatureNutrientNutrient availabilityPathway interactionsPatientsPhenotypeProliferatingProtein IsoformsRegulationReportingResistanceRoleSLC2A1 geneSafetySolid NeoplasmSurveysSurvival RateT cell therapyT-Cell ActivationT-LymphocyteTestingTherapeuticTumor ImmunityTumor-infiltrating immune cellsaerobic glycolysiscancer cellcancer immunotherapycancer therapycancer typechimeric antigen receptorchimeric antigen receptor T cellsclinical applicationdesigneffector T cellengineered T cellsexperienceflexibilityglucose metabolismimprovedin vivoinnovationinterestmetabolic engineeringmetabolic fitnessmouse modelneoplastic celloverexpressionpressureprognosticprogramsrestraintsuccesstherapy resistantthymocytetumortumor microenvironmentuptake
项目摘要
PROJECT SUMMARY AND ABSTRACT
Significance: Glioblastoma (GBM) is an extremely devastating disease with reported median survivals ranging
from 13 to 73 months and 5-year survivals of less than 20% in children and about 15 months with less than 5%
5-year survival rate for adult patients. Cancer immunotherapy using chimeric antigen receptor (CAR) modified T
cells is a promising treatment, however its efficacy in GBM has been limited.
Hypothesis: We hypothesize that the fierce competition for nutrients within the tumor microenvironment,
especially glucose, between tumor cells and the immune system, imposes an abundant metabolic pressure to
CAR T cells dampening their effector function and intratumoral infiltration, expansion, and persistence.
Objective: The goal of this study is to validate a new strategy to overcome this metabolic imbalance and provide
a competitive advantage to CAR T cells over tumor cells. We propose to improve CAR T cell therapy by
enhancing metabolic fitness to outcompete GBM cells for nutrients like glucose.
Methods: Our approach will be to directly target the first step of glucose metabolism (i.e., uptake) by permanent
overexpression of GLUT1 or GLUT3 and generating the following CAR T cells: CD70CAR.G1 and CD70CAR.G3.
The murine model of glioma KR158B, derived from Nf1;Trp53 mutant mouse, that we engineered to express
CD70 as well as CD70 expressing human GBM patient-derived cell lines will be used for the following aims:
Specific Aims
1. Investigate the phenotypic and functional characteristics of metabolically modified CD70CAR T cells,
2. Evaluate in vivo the metabolic TME of animals treated with CD70CAR.G1 or CD70CAR.G3,
3. Examine the safety and anti-tumor efficacy of CD70CAR.G1 or CD70CAR.G3.
项目总结和摘要
意义:胶质母细胞瘤(GBM)是一种极具破坏性的疾病,据报道,
儿童13至73个月和5年生存率低于20%,约15个月生存率低于5%
5-成年患者的年生存率。使用嵌合抗原受体(CAR)修饰的T细胞的癌症免疫疗法
细胞是一种有前途的治疗方法,但其在GBM中的疗效有限。
假设:我们假设肿瘤微环境中对营养物质的激烈竞争,
特别是葡萄糖,在肿瘤细胞和免疫系统之间,施加了大量的代谢压力,
CAR T细胞抑制其效应子功能和肿瘤内浸润、扩增和持久性。
目的:本研究的目的是验证克服这种代谢失衡的新策略,
CAR T细胞相对于肿瘤细胞的竞争优势。我们建议通过以下方式改善CAR T细胞疗法:
增强代谢适应性以在营养物如葡萄糖的竞争中胜过GBM细胞。
方法:我们的方法将直接针对葡萄糖代谢的第一步(即,吸收)
G1和CD70CAR.G3。
神经胶质瘤小鼠模型KR 158 B,来源于Nf 1; Trp 53突变小鼠,我们设计表达
CD 70以及表达CD 70的人GBM患者来源细胞系将用于以下目的:
具体目标
1.研究代谢修饰的CD 70 CAR T细胞的表型和功能特征,
2.在体内评价用CD70CAR.G1或CD70CAR.G3处理的动物的代谢TME,
3.检查CD70CAR.G1或CD70CAR.G3的安全性和抗肿瘤疗效。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Loic Pierre Deleyrolle其他文献
Loic Pierre Deleyrolle的其他文献
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{{ truncateString('Loic Pierre Deleyrolle', 18)}}的其他基金
Metabolic interactions between tumor cells and the immunce system in GBM A potential Achilles heel of GBM for novel therapeutics
GBM 中肿瘤细胞与免疫系统之间的代谢相互作用是 GBM 新疗法的潜在致命弱点
- 批准号:
10522529 - 财政年份:2022
- 资助金额:
$ 17.82万 - 项目类别:
Metabolic interactions between tumor cells and the immunce system in GBM A potential Achilles heel of GBM for novel therapeutics
GBM 中肿瘤细胞与免疫系统之间的代谢相互作用是 GBM 新疗法的潜在致命弱点
- 批准号:
10673172 - 财政年份:2022
- 资助金额:
$ 17.82万 - 项目类别:
Slow cycling cell RNA based T cell therapy to prevent recurrence in GBM
基于慢循环细胞 RNA 的 T 细胞疗法可预防 GBM 复发
- 批准号:
10331046 - 财政年份:2021
- 资助金额:
$ 17.82万 - 项目类别:
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