Modulating extracellular TCR-CD3 interactions to identify new melanoma immunotherapy targets
调节细胞外 TCR-CD3 相互作用以确定新的黑色素瘤免疫治疗靶点
基本信息
- 批准号:10290708
- 负责人:
- 金额:$ 23.77万
- 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:2021-06-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAmino AcidsAntigen TargetingAntigensBindingBinding SitesBiological AssayCD3 AntigensCTLA4 geneCell surfaceClone CellsComplementarity Determining RegionsComputing MethodologiesDataDockingEffectivenessExploratory/Developmental GrantGenerationsGoalsHLA-A2 AntigenHumanImmuneImmune System DiseasesImmune signalingImmune systemImmunityImmunoglobulin Variable RegionImmunosuppressionImmunotherapeutic agentImmunotherapyIn VitroInterferonsInterleukin-2KnowledgeLaboratoriesLeadLibrariesMajor Histocompatibility ComplexMalignant NeoplasmsMechanicsMediatingMetastatic MelanomaMethodologyMethodsMusMutagenesisMutateMutationNuclear Magnetic ResonanceOutcomePathway interactionsPatientsPeptidesPhase I Clinical TrialsProteinsPublishingRegimenRegulatory T-LymphocyteResistanceSILV geneSignal PathwaySignal TransductionSiteSkin CancerSpecificityStructureSystemT Cell Receptor Signaling PathwayT cell responseT cell therapyT-Cell ReceptorT-LymphocyteTestingThymus GlandToxic effectTumor Antigensadaptive immune responseanti-CTLA4anti-PD-1basecross reactivitycytokinecytotoxicitydesigndimerengineered T cellsextracellularfight againstfunctional outcomeshigh rewardhigh riskimmune checkpoint blockadeimprovedin silicoin vivoin vivo Modelinnovationmelanomamonomermouse modelmutantneoplastic cellnovelnovel strategiesprogrammed cell death protein 1programsprotein complexreceptor bindingresponsescreeningsmall moleculetumortumor initiation
项目摘要
ABSTRACT
Melanoma is one of the deadliest and aggressive form of skin cancer. Main treatment options in metastatic
melanoma involve T cell immunotherapy using checkpoint blockade (anti-PD-1, anti-CTLA-4 and others) or
adoptive T cell therapy (ACT) with modified patient T cells. Although, durable response is only observed in a
fraction of patients. Further progress can be made by studying and targeting different T cell signaling
pathways. One such pathway is the T cell receptor (TCR) signaling pathway. T cell recognition of antigen by
the TCR and the resulting proximal signaling through the surrounding CD3 subunits are key steps in the
initiation of tumor-killing. Identification of the specific extracellular contacts between the TCR and CD3 subunits
gives precise guidance for immunotherapeutic strategies that modulate T-cell immunity by targeting signaling
through the TCR-CD3 complex. Previous studies that targeted the antigen binding site for enhancing T-cell
responses to tumor antigens often lead to off-target effects and toxicity. Based on our recent TCR-CD3
structure, we mutated specific CD3 interacting TCR-residues that resulted in different T cell cytokine
responses. Our hypothesis is that by modulating TCR-CD3 interactions in specific ways, immune-mediated
cytotoxicity to tumor antigens can be increased without losing specificity for the cancer antigen. To test our
hypothesis, in Aim 1, an in vitro retroviral TCR display method and a novel CD3-tetramer assay will be used to
mutate specific TCR-residues and identify TCRs that interact with CD3 with increased affinity, resulting in T
cells that mediate more effective functionality. In Aim 2, a structure-based TCR design will be used to identify
TCR mutants with enhanced CD3 binding ability in silico. In both instances, identified mutations will be
introduced into gp100-specific TCRs and their in vitro/in vivo tumor killing efficacy will be analyzed to validate
the anti-tumor potential of new TCRs with the goal of developing new wave of effective T cell therapies against
melanoma.
摘要
黑色素瘤是皮肤癌中最致命和最具侵略性的形式之一。转移性肿瘤的主要治疗选择
黑色素瘤涉及使用检查点阻断(抗PD-1、抗CTLA-4等)的T细胞免疫疗法,或
使用修饰的患者T细胞进行过继性T细胞治疗(ACT)。虽然,持久的反应只观察到在一个
部分患者。通过研究和靶向不同的T细胞信号传导,
途径。一种这样的途径是T细胞受体(TCR)信号传导途径。T细胞对抗原的识别
TCR和通过周围CD 3亚基产生的近端信号传导是免疫应答的关键步骤。
启动肿瘤杀伤。TCR和CD 3亚基之间特异性细胞外接触的鉴定
为通过靶向信号调节T细胞免疫的免疫策略提供了精确的指导
通过TCR-CD 3复合物。以前的研究靶向抗原结合位点以增强T细胞
对肿瘤抗原的反应通常导致脱靶效应和毒性。根据我们最近的TCR-CD 3
结构,我们突变了特异性CD 3相互作用TCR残基,导致不同的T细胞细胞因子,
应答我们的假设是,通过以特定的方式调节TCR-CD 3相互作用,免疫介导的免疫应答可能会增加。
可以增加对肿瘤抗原的细胞毒性而不丧失对癌抗原的特异性。来测试我们
假设,在目标1中,体外逆转录病毒TCR展示方法和新的CD 3-四聚体测定将用于
突变特异性TCR残基,并鉴定与CD 3相互作用的TCR,其亲和力增加,导致T
介导更有效功能的细胞。在目标2中,将使用基于结构的TCR设计来识别
计算机模拟具有增强的CD 3结合能力的TCR突变体。在这两种情况下,鉴定出的突变将是
并将分析它们的体外/体内肿瘤杀伤功效以验证
新TCR的抗肿瘤潜力,目标是开发新一波有效的T细胞疗法,
黑素瘤
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)
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Aswin Natarajan其他文献
Aswin Natarajan的其他文献
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{{ truncateString('Aswin Natarajan', 18)}}的其他基金
Modulating extracellular TCR-CD3 interactions to identify new melanoma immunotherapy targets
调节细胞外 TCR-CD3 相互作用以确定新的黑色素瘤免疫治疗靶点
- 批准号:
10406370 - 财政年份:2021
- 资助金额:
$ 23.77万 - 项目类别:
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