Oncofetal TNC CAR T Cell Therapy for Pediatric Sarcoma
治疗儿童肉瘤的肿瘤胎儿 TNC CAR T 细胞疗法
基本信息
- 批准号:10683408
- 负责人:
- 金额:$ 4.37万
- 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:2021-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptive Cell TransfersAdoptive ImmunotherapyAdultAntigensBiological AssayBrainCAR T cell therapyCD19 geneCD28 geneCRISPR/Cas technologyCell LineCell Surface ProteinsCell Surface ReceptorsCell TherapyCell surfaceCellsCellular immunotherapyCessation of lifeChildhoodChildhood Solid NeoplasmClinicClinical ResearchCoculture TechniquesComprehensive Cancer CenterCritical ThinkingEducational process of instructingEndowmentEngineeringEnzyme-Linked Immunosorbent AssayEwings sarcomaExocytosisExtracellular MatrixExtracellular Matrix ProteinsFaceFetal DevelopmentFibronectinsFlow CytometryFoundationsFutureGenerationsGenesGoalsGranzymeHematologic NeoplasmsHumanImageImmunohistochemistryImmunologicsImmunotherapyIn VitroKnowledgeLigandsMalignant NeoplasmsManuscriptsMeasurementMediatingModelingMolecular Biology TechniquesMonitorMonoclonal AntibodiesMusNormal CellNormal tissue morphologyPathway interactionsPre-Clinical ModelPrognosisProtein SecretionProteinsRNA SplicingRecurrenceRefractoryResearchResearch PersonnelRhabdomyosarcomaSafetySaint Jude Children&aposs Research HospitalScientistSignal TransductionSolidSolid NeoplasmSpicesSystemT-LymphocyteTechniquesTenascinToxic effectTrainingTumor AngiogenesisVariantXenograft Modelbioluminescence imagingcancer cellcancer immunotherapycell killingcell motilitychildhood sarcomachimeric antigen receptorchimeric antigen receptor T cellscytokinecytotoxicitydesigndifferential expressioneffector T cellexperimental studygenome editinggranule cellimprovedin vivomalignant phenotypeneoplastic cellnovelosteosarcomapatient populationperforinpre-clinicalreceptorresearch clinical testingsarcomasecretory proteinsubcutaneoussuccesstumortumor immunologytumor microenvironment
项目摘要
Project Abstract
The long-term goal of this project is to develop an adoptive immunotherapy with T cells expressing chimeric
antigen receptors (CARs) for recurrent and refractory pediatric sarcoma, which prognosis remains poor. CAR T
cell therapy has demonstrated success for hematological malignancies in clinical studies; however, CAR T cells
have been less effective for solid tumors in the clinic. While limited efficacy is multifactorial, a significant
roadblock for solid tumor CAR T cell therapy is the lack of targetable antigens. One prominent ECM protein is
tenascin C (TNC), and cancer cells, including sarcoma cells, express oncofetal tenascin C (TNC) spice
variants, which can contain an additional C domain (C.TNC). Since C.TNC expression correlates with the
malignant phenotype of cancer cells, we posit that it is an ideal CAR target. In support of this application, we
have generated a 2nd generation C.TNC-specific CAR with a CD28 costimulatory domain (C.TNC-CAR). I now
hypothesize that C.TNC-CAR T cells recognize and kill C.TNC-positive tumor cells and can be
optimized to have potent antitumor in preclinical pediatric sarcoma models. We have demonstrated in
preliminary studies that C.TNC-CAR T cells recognize and kill C.TNC+ sarcoma cell lines in vitro. In this project
now, we propose to investigate this hypothesis in two interrelated research aims. Aim 1 focuses on
understanding the mechanism of our ECM-targeting C.TNC-CAR T cells, and Aim 2 then compares the
effector function of C.TNC-CAR T cells in in vivo sarcoma xenograft models evaluating expansion,
persistence, and anti-tumor activity. Techniques to be employed include flow cytometry, ELISAs, co-cultures
and cytotoxicity assays, and CRISPR-Cas9 genome editing.
This project was designed to train me in techniques to generate and characterize genetically modified T cells
expressing CARs as well as introduce me into the evolving field of cancer cell therapy. This proposal and training
will be performed at St. Jude Children’s Research Hospital, an NCI-designated comprehensive cancer center. If
successful, the results of this proposal could have immediate applications for pediatric sarcomas. In addition, it
should have a significant impact on a broad range of other pediatric and adult solid tumors that also express
C.TNC.
项目摘要
该项目的长期目标是开发一种表达嵌合T细胞的过继免疫疗法
抗原受体(CARS)治疗复发和难治性儿童肉瘤,其预后仍然很差。T型车
细胞疗法已经在临床研究中证明了对血液系统恶性肿瘤的成功;然而,CAR T细胞
在临床上对实体瘤的疗效较差。虽然有限的疗效是多因素的,但显著的
实体瘤CAR T细胞治疗的障碍是缺乏靶向抗原。一种重要的ECM蛋白是
TnC和包括肉瘤细胞在内的癌细胞表达肿瘤胎儿TnC(TNC)SPICE
变种,可以包含一个额外的C结构域(C.TNC)。由于C.TNC表达与
肿瘤细胞的恶性表型,我们认为它是一个理想的CAR靶点。为了支持这一应用程序,我们
已经产生了具有CD28共刺激结构域的第二代C.TNC特异性CAR(C.TNC-CAR)。我现在
假设C.TNC-CAR T细胞识别和杀伤C.TNC阳性的肿瘤细胞,并可以
在临床前儿童肉瘤模型中优化为具有有效的抗肿瘤作用。我们已经在
C.TNC-CAR细胞体外识别和杀伤C.TNC+肉瘤细胞系的初步研究在这个项目中
现在,我们打算从两个相互关联的研究目标来考察这一假说。目标1侧重于
了解我们的ECM靶向C.TNC-CAR T细胞的机制,并将目标2与
C.TNC-CAR T细胞在肉瘤体内移植模型中的效应功能
持久力强,具有抗肿瘤活性。可采用的技术包括流式细胞术、ELISA、共培养
和细胞毒性试验,以及CRISPR-Cas9基因组编辑。
这个项目的目的是训练我如何产生和鉴定转基因T细胞
表达汽车,并将我带入不断发展的癌症细胞治疗领域。这份建议书和培训
将在圣犹大儿童研究医院进行,圣犹大儿童研究医院是NCI指定的综合性癌症中心。如果
如果成功,这项提议的结果可能立即应用于儿童肉瘤。此外,它还
应该对广泛的其他儿童和成人实体肿瘤有显著影响,这些肿瘤也表达
C.TNC。
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)
专利数量(0)
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Elizabeth Wickman其他文献
Elizabeth Wickman的其他文献
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{{ truncateString('Elizabeth Wickman', 18)}}的其他基金
Oncofetal TNC CAR T Cell Therapy for Pediatric Sarcoma
治疗儿童肉瘤的肿瘤胎儿 TNC CAR T 细胞疗法
- 批准号:
10314818 - 财政年份:2021
- 资助金额:
$ 4.37万 - 项目类别:
Oncofetal TNC CAR T Cell Therapy for Pediatric Sarcoma
治疗儿童肉瘤的肿瘤胎儿 TNC CAR T 细胞疗法
- 批准号:
10532677 - 财政年份:2021
- 资助金额:
$ 4.37万 - 项目类别: