Improving genetically engineered T cells for medulloblastomas
改善髓母细胞瘤基因工程 T 细胞
基本信息
- 批准号:10390362
- 负责人:
- 金额:$ 44.48万
- 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:2021-04-15 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAntigensAntitumor ResponseB lymphoid malignancyBrain NeoplasmsCD276 geneCSF1R geneCancerousCell TherapyCell physiologyCellsChildChildhood Brain NeoplasmChildhood Malignant Brain TumorClinical ResearchCombined Modality TherapyCytosineDNADNA Modification MethylasesDioxygenasesERBB2 geneEngineered GeneEngineeringEpigenetic ProcessFrequenciesFutureGeneticGenetic EngineeringHealthImmuneImmune responseImmune systemImmunocompetentImmunotherapyInfusion proceduresInnovative TherapyInstitutionKnowledgeLeadLeftMacrophage Colony-Stimulating FactorMalignant NeoplasmsMediatingMediator of activation proteinMethodsMethyltransferaseModificationMolecularMusNeoplasm MetastasisPatientsPerformancePhase I Clinical TrialsPre-Clinical ModelProductionRelapseResistanceResourcesSignal TransductionSpecificityT-Cell Immunologic SpecificityT-LymphocyteTestingTetanus Helper PeptideTextTherapeuticTissuesTumor AntigensTumor-associated macrophagesXenograft procedureangiogenesisantigen challengeantigen-specific T cellsantitumor effectbasecancer cellcancer therapychimeric antigen receptorchimeric antigen receptor T cellsconventional therapycytokineeffector T cellengineered T cellsexhaustionexperienceexperimental studyimmunoengineeringimprovedimproved outcomeinhibitorinsightleukemiamedulloblastomamouse modelnegative affectnovel therapeutic interventionpre-clinicalpreclinical studyprogramsreceptorrecruitsafety engineeringside effectsuccesstooltumortumor microenvironmenttumor progressiontumor-immune system interactions
项目摘要
Title: Improving genetically engineered T cells for medulloblastoma
PROJECT SUMMARY/ABSTRACT
The intent of this project is to develop antigen-specific T cells as an effective immunotherapy for medulloblastoma
(MB), a most common pediatric brain tumor. While recent advances in MB treatment slightly improved the overall
survival, the patients are left with long-term devastating side effects as a result of a treatment. The body’s natural
immune defenses against cancer often fail because the cancer either does not provoke or actively inhibits
immune responses. However, genetic modification of the patient’s own immune system can be used to endow
T cells with improved ability to recognize and kill cancerous cells that would not otherwise respond to
conventional therapies. Cancer treatments consisting of the infusion of T cells that are engineered to recognize
tumor antigens, molecules present only on cancers cells, have shown dramatic success in clinical studies against
leukemia. We now propose to develop such approach for MB. In our method, we will target two antigens called
IL13Ra2 and B7-H3 which are present on MB cells. Next, we will improve our approach by deleting epigenetic
regulators that are known to suppress T cell effector function. Finally, we will use an immunocompetent MB
mouse model to ask which immune cells within brain tumor microenvironment (TME) control CAR T cell efficacy.
Brain tumors are notorious for having an immunosuppressive TME, yet its effect on engineered immune cells
are poorly understood. Thus, the use of mouse models with functional immune system will allow us to accurately
evaluate the function and safety of engineered T cells as well as understand the brain TME. In summary, we
propose to first establish CAR T cells targeting two antigens in order to improve their specificity (Aim 1). We will
then improve their persistence through ablation of epigenetic programs (Aim 2). We will also perform a detailed
mechanistic study to determine how epigenetic regulators control effector function of engineered CAR T cells.
Finally, we will investigate if elimination of key inhibitory immune cells within the brain TME will enhance anti-
tumor effects of CAR T cells (Aim 3). We expect that our proposed studies using gene engineered bi-specific
CAR T cells and immunocompetent mouse model will provide mechanistic insight and superior understanding
on how engineered T cells function and interact with the brain TME. We believe that such knowledge will lead
not only to the creation of improved immune cell-based approaches but also to potential novel therapeutic
approaches for brain tumors in the future. If our pre-clinical approach is successful, we have the resources to
develop a Phase I clinical trial at our institution.
题目:改良基因工程T细胞治疗成神经管细胞瘤
项目成果
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{{ truncateString('Giedre Krenciute', 18)}}的其他基金
Targeting tumor and T cell DNA methylomes to improve CAR T cell therapies for diffuse midline glioma
靶向肿瘤和 T 细胞 DNA 甲基化组以改善弥漫性中线神经胶质瘤的 CAR T 细胞疗法
- 批准号:
10715739 - 财政年份:2023
- 资助金额:
$ 44.48万 - 项目类别:
Improving genetically engineered T cells for medulloblastomas
改善髓母细胞瘤基因工程 T 细胞
- 批准号:
10581552 - 财政年份:2021
- 资助金额:
$ 44.48万 - 项目类别:
Improving genetically engineered T cells for medulloblastomas
改善髓母细胞瘤基因工程 T 细胞
- 批准号:
10181761 - 财政年份:2021
- 资助金额:
$ 44.48万 - 项目类别:
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