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
基本信息
- 批准号:10715739
- 负责人:
- 金额:$ 80.77万
- 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:2023-09-07 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:Animal ModelBiological ModelsBrain NeoplasmsCAR T cell therapyCell TherapyCell physiologyCellsChemicalsChildhood Brain NeoplasmClinical ResearchDNADNA MethylationDNA Methylation InhibitionDNA Modification ProcessDataDevelopmentDiseaseElementsEnvironmentEpigenetic ProcessEvaluationFrequenciesFutureGeneticGenetic TranscriptionGoalsH3 K27M mutationImmuneImmune checkpoint inhibitorImmune responseImmune systemImmunocompetentImmunologic StimulationImmunotherapyIn VitroMalignant Childhood NeoplasmMalignant NeoplasmsModelingMolecularPatientsPhenotypePopulationPre-Clinical ModelProcessRecurrent tumorResistanceSolid NeoplasmT-Cell ActivationT-LymphocyteTechnologyTestingTherapeuticTransferaseTranslatingTranslational ResearchWorkXenograft procedurecancer cellchimeric antigen receptorchimeric antigen receptor T cellscombinatorialdemethylationdiffuse midline gliomaeffective therapyeffector T cellepigenomeexhaustiongenetic selectionhuman diseaseimmune cell infiltrateimprovedin vivoinhibitorinnate immune pathwaysinnovationinsightmethylomemouse modelmultidisciplinaryneoplastic cellnovelpharmacologicpreventprogramsrecruitresponsetranslational medicinetumortumor DNAtumor microenvironment
项目摘要
SUMMARY/ABSTRACT
While improvements in immune therapies have revolutionized treatments in some cancers, pediatric brain tumors
are especially resistant to current immunotherapy treatments, including immune check point inhibitors. This may
be because many pediatric brain tumors have been characterized as “immune cold”, with little to no immune cell
infiltration. Chimeric antigen receptor (CAR) T cell therapies have shown promise against fatal brain tumors such
as diffuse midline glioma (DMG) in early clinical studies. However, in early studies, patients inevitably succumb
to this fatal disease. This raises important questions about mechanisms of CAR T cell resistance and devising
strategies to improve and prolong CAR T cell function. Targeting epigenetic programs has been identified as one
strategy to overcome deficient immune responses in solid tumors through both tumor cell intrinsic and tumor
microenvironment mechanisms. We have shown in DMG that inhibition of DNA methylation activates innate
immune pathways that may stimulate immune cell recruitment and activity (Krug et al., Cancer Cell, 2019). Our
data in CAR T cells deficient for a DNA methyl transferase (DNMT3A) displays reduced exhaustion and
enhanced anti-tumor activity against multiple tumor models, including brain tumors (Prinzing et al., Science
Translational Medicine, 2021). We hypothesize that combinatorial approaches that target distinct DMG and
CAR T cell DNA methylomes represents a rational strategy to enhance CAR T cell therapy. We propose to test
this in two specific aims: AIM1: Determine how tumor DNA demethylation in DMG impacts CAR T cell recruitment
and function. We will test the hypothesis that inhibition of DNA methylation induced endogenous retroviral
activation will enhance CART cell activation and persistence. AIM2: Determine if CAR T cell effector function is
improved by DNA methylation inhibition in DMG. We will test the hypothesis that inhibition of DNA methylation
in CAR T cells is a phenotype that translates to DMG, by preventing T cell exhaustion and improving long-term
effector function.
摘要/文摘
项目成果
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{{ truncateString('Giedre Krenciute', 18)}}的其他基金
Improving genetically engineered T cells for medulloblastomas
改善髓母细胞瘤基因工程 T 细胞
- 批准号:
10390362 - 财政年份:2021
- 资助金额:
$ 80.77万 - 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:
$ 80.77万 - 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:
$ 80.77万 - 项目类别:
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