Enhancing mitochondrial metabolism to improve anti-tumor CD8 immune response
增强线粒体代谢,提高抗肿瘤CD8免疫反应
基本信息
- 批准号:10578743
- 负责人:
- 金额:$ 37.04万
- 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:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:ATP Synthesis PathwayAcute Lymphocytic LeukemiaAffectB-Cell LeukemiaCAR T cell therapyCD19 geneCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCancer ModelCell SurvivalCell physiologyCellsCellular Metabolic ProcessCellular biologyChronicClinical TrialsComplexCytoplasmic GranulesCytosolCytotoxic ChemotherapyDataEngineeringEnvironmentExocytosisFDA approvedFailureGenerationsGlucoseGlycolysisGoalsHumanImmuneImmune responseImmunologyImmunotherapyIn VitroIn complete remissionInner mitochondrial membraneIntegral Membrane ProteinInterleukin-2Knockout MiceMaintenanceMalignant NeoplasmsMembrane PotentialsMemoryMetabolicMetabolic PathwayMetabolismMethylationMitochondriaMultiple MyelomaMusNADH dehydrogenase (ubiquinone)Non-Hodgkin&aposs LymphomaNonesterified Fatty AcidsNucleotide BiosynthesisOutcomeOxidative PhosphorylationPathway interactionsPatientsProductionProtein DeficiencyProteinsRefractoryRegimenRelapseRespirationRoleSourceT-Cell ProliferationT-LymphocyteTestingTherapeuticTreatment FailureXenograft Modelcancer cellcancer immunotherapychimeric antigen receptor T cellsclinical translationclinically relevantconventional therapycytokinecytotoxiccytotoxicityeffector T cellefficacy evaluationfatty acid oxidationhealthy volunteerimmune functionimprovedin vivoinfluenzavirusinterestleukemia/lymphomamelanomamitochondrial membranemitochondrial metabolismmouse modelneoplastic celloptimal treatmentsprotein expressionrelapse preventionsuccesstumor
项目摘要
SUMMARY
CAR-T immunotherapy has great promise as a salvage regimen for patients who will no longer respond to
conventional therapies. Five CAR-T cell therapies (four targeting CD19 on cancer cells) have been approved
by FDA for treatment of relapsed and/or refractory (r/r) B-lineage malignancies, including ALL, Non-Hodgkin
Lymphoma, CLL and multiple myeloma. However, about 50% of B cell leukemia and lymphoma patients
treated with CD19 CAR-T therapy relapse within a year after CAR-T therapy. The success of CAR-T therapy
has been associated with several factors, including: 1) the initial expansion of CAR-T cells after transfer into
the patients in an IL-2-deprived environment, 2) maintenance of the CAR-T cell effector function 3) long-term
survival of CAR-T cells. These T cell biology aspects are highly influence by their metabolic stage, and CAR-T
cell outcome is known to be influenced by their metabolism. Metabolism is now considered as a major
regulatory factor of the function of immune cells and influences the course of an immune response. We have
identified MCJ (Methylation-Controlled J protein) as a protein localized in the inner membrane of mitochondria
that acts as an endogenous negative regulator of Complex I and mitochondrial respiration (mitochondrial ATP
production). We have shown that loss of MCJ in CD8 cells enhances cytokine secretion as well as cytotoxic
activity. Memory MCJ KO CD8 cells have superior protective activity against influenza virus. MCJ deficient
CD8 cells are also more efficient in killing tumor cells. Thus, we hypothesize that eliminating MCJ as a
metabolic brake in CD8 cells will result in enhanced cytokine production, tumor killing activity and survival of
CAR-T cells and that MCJ could be an attractive target to improve the success of CAR-T immunotherapy. To
test this hypothesis and show its clinical relevance, we propose: 1) to evaluate the role of MCJ as a regulator
of mitochondrial metabolism and effector function in human CD8 cells; 2) to evaluate the in vitro and vivo
potency and efficacy of mouse MCJ-deficient CAR T cells, 3) to develop an MCJ-deficient human CD8 CAR-T
with improved survival, expansion and cytotoxic activity.
总结
CAR-T免疫疗法作为一种挽救方案,对于那些不再对化疗有反应的患者具有很大的前景。
传统疗法。五种CAR-T细胞疗法(四种靶向癌细胞上的CD 19)已获得批准
FDA批准用于治疗复发性和/或难治性(r/r)B系恶性肿瘤,包括ALL、非霍奇金淋巴瘤
淋巴瘤、CLL和多发性骨髓瘤。然而,约50%的B细胞白血病和淋巴瘤患者
接受CD 19 CAR-T治疗的患者在CAR-T治疗后一年内复发。CAR-T疗法的成功
已经与几个因素相关,包括:1)CAR-T细胞在转移到
患者处于IL-2剥夺环境中,2)CAR-T细胞效应子功能的维持,3)长期
CAR-T细胞的存活。这些T细胞生物学方面受到其代谢阶段的高度影响,并且CAR-T
已知细胞结果受到其新陈代谢的影响。代谢现在被认为是一个主要的
免疫调节因子是免疫细胞功能的调节因子,并影响免疫应答的过程。我们有
发现MCJ(甲基化控制的J蛋白)是一种定位于线粒体内膜的蛋白质
其作为复合物I和线粒体呼吸(线粒体ATP)的内源性负调节剂
生产)。我们已经表明,CD 8细胞中MCJ的缺失增强了细胞因子分泌以及细胞毒性。
活动记忆MCJ KO CD 8细胞对流感病毒具有上级保护活性。MCJ缺陷
CD 8细胞在杀死肿瘤细胞方面也更有效。因此,我们假设,消除MCJ作为一个
CD 8细胞中的代谢制动将导致增强的细胞因子产生、肿瘤杀伤活性和肿瘤细胞的存活。
CAR-T细胞和MCJ可能是一个有吸引力的目标,以提高CAR-T免疫治疗的成功。到
为了验证这一假设并显示其临床意义,我们建议:1)评估MCJ作为调节剂的作用
人CD 8细胞中线粒体代谢和效应子功能的研究; 2)评估体外和体内
小鼠MCJ缺陷型CAR T细胞的效力和功效,3)开发MCJ缺陷型人CD 8 CAR-T
具有改善的存活、扩增和细胞毒活性。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Mercedes Rincon其他文献
Mercedes Rincon的其他文献
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{{ truncateString('Mercedes Rincon', 18)}}的其他基金
Targeting mitochondrial regulator MCJ to enhance CD8 cell immune response
靶向线粒体调节剂 MCJ 增强 CD8 细胞免疫反应
- 批准号:
10293952 - 财政年份:2020
- 资助金额:
$ 37.04万 - 项目类别:
Fine-tuning of mitochondrial Complex I activity in CD8 cells
CD8 细胞中线粒体复合物 I 活性的微调
- 批准号:
10092947 - 财政年份:2020
- 资助金额:
$ 37.04万 - 项目类别:
Fostering entrepreneurship in biomedical research
培养生物医学研究创业精神
- 批准号:
8998210 - 财政年份:2016
- 资助金额:
$ 37.04万 - 项目类别:
IL-6: an innate immune regulator for the plasticity of Tfh cells
IL-6:Tfh 细胞可塑性的先天免疫调节剂
- 批准号:
8434542 - 财政年份:2012
- 资助金额:
$ 37.04万 - 项目类别:
COBRE: UVT: CORE TRANSGENIC ANIMAL PROGRAM: MOUSE GENOMIC DNA BAC LIBRARY
COBRE:UVT:核心转基因动物计划:小鼠基因组 DNA BAC 文库
- 批准号:
7959621 - 财政年份:2009
- 资助金额:
$ 37.04万 - 项目类别:
MCJ function in mouse mammary tumor properties
MCJ 在小鼠乳腺肿瘤特性中的功能
- 批准号:
7807612 - 财政年份:2008
- 资助金额:
$ 37.04万 - 项目类别:
COBRE: UVT: CORE TRANSGENIC ANIMAL PROGRAM: MOUSE GENOMIC DNA BAC LIBRARY
COBRE:UVT:核心转基因动物计划:小鼠基因组 DNA BAC 文库
- 批准号:
7720875 - 财政年份:2008
- 资助金额:
$ 37.04万 - 项目类别:
MCJ function in mouse mammary tumor properties
MCJ 在小鼠乳腺肿瘤特性中的功能
- 批准号:
7390544 - 财政年份:2008
- 资助金额:
$ 37.04万 - 项目类别:
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