A Pilot Study of 5-FC and Genetically-Modified Neural Stem Cells to Treat Gliomas
5-FC 和转基因神经干细胞治疗神经胶质瘤的初步研究
基本信息
- 批准号:7737841
- 负责人:
- 金额:$ 36.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2011-06-30
- 项目状态:已结题
- 来源:
- 关键词:Advisory CommitteesAllogenicAngiogenic FactorAnimalsAntineoplastic AgentsBiodistributionBlood - brain barrier anatomyBrainBrain NeoplasmsBystander EffectCarboxylic Ester HydrolasesCell LineCellsCentral Nervous System NeoplasmsClinicalClinical TrialsCohort StudiesCraniotomyCytosine deaminaseDataDialysis procedureDifferentiation InducerDiffuseDisease ProgressionDistantDoseDrug Delivery SystemsEffectivenessEnzymesExcisionFeasibility StudiesFlucytosineFluorouracilFutureGliomaGoalsHumanImmuneIronKnowledgeLabelMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMalignant - descriptorMeasuresMediatingMediator of activation proteinMetastatic malignant neoplasm to brainMicrodialysisModelingMusNatureNeoplasm MetastasisNeuraxisNeuroblastomaOncologistOncolyticOperative Surgical ProceduresOralPatientsPharmaceutical PreparationsPilot ProjectsPrimary Brain NeoplasmsProdrugsPropertyProtonsRecombinant DNARecurrenceResearchResearch Project GrantsResearch ProposalsResidual TumorsSN-38SafetySignal TransductionSiteSolid NeoplasmSpecificitySurgically-Created Resection CavityTestingTherapeuticTherapeutic AgentsTherapeutic IndexTherapeutic StudiesToxic effectTropismTumor DebulkingUnited States National Institutes of HealthWeightbasebrain tissuecancer therapycarboxylesterasecell motilitychemotherapeutic agentfetalgene therapyimmunogenicimprovedirinotecankillingsmedulloblastomameetingsnanoparticleneoplastic cellnerve stem cellnovelpre-clinicalpreventpublic health relevancesuccesstherapeutic enzymetherapeutic transgenetreatment strategytumortumorigenicv-myc Gene
项目摘要
DESCRIPTION (provided by applicant): The diffuse, infiltrative nature of high-grade gliomas is a major obstacle to curing these tumors. In order to make a significant impact on survival, new treatment strategies must specifically target these extremely invasive tumor cells. Human neural stem cells (NSCs) hold great promise for glioma therapy because of their inherent ability to target tumor cells throughout the brain. By harnessing their tumor-tropism and genetically modifying them to express a therapeutic transgene, NSCs can act as delivery vehicles for targeted anti-cancer therapies. NSC-mediated treatment approaches can potentially increase tumor-selectivity, decrease toxicities, and achieve therapeutic indices sufficient to eradicate invasive and residual tumor cells. We propose the use of a well-characterized, clonal, allogeneic NSC line (HB1.F3) that has been retrovirally-transduced to stably express the enzyme, cytosine deaminase (CD), which converts the oral prodrug 5- fluorocytosine (5-FC) to the chemotherapeutic agent 5-fluorouracil (5-FU). Preliminary data in normal and orthotopic glioma murine models indicate that this cell line is safe, non-tumorigenic, non-immunogenic, and therapeutically active. In Specific Aim 1 of this research project, a pilot feasibility study in recurrent high-grade glioma patients will be performed to determine the safety of intracerebral administration of HB1.F3.CD NSCs in combination with 5-FC. Three dose levels of NSCs will be tested. Specific Aim 2 will demonstrate proof-of-concept by assessing the extent to which the CD-expressing NSCs convert 5-FC to 5-FU at sites of tumor. Intracerebral levels of 5-FC and 5-FU will be measured by micro dialysis, and we will characterize the relationship between intracerebral and systemic concentrations of 5-FC and 5-FU with increasing NSC dose level. 19F MRS will also be used to non-invasively document the presence of 5-FU in the brain during 5-FC treatment. PUBLIC HEALTH RELEVANCE: Human fetal neural stem cells (NSCs) are inherently tumor-tropic. When modified to express a therapeutic transgene, NSCs have the potential to be used as delivery vehicles for anti-cancer therapies. We propose the clinical use of a well-characterized, clonal, allogeneic NSC line, HB1.F3, which has been modified to express cytosine deaminase (CD). CD converts the inactive prodrug 5-fluorocytosine (5-FC) to the active chemotherapeutic 5-fluorouracil (5-FU). Preliminary biodistribution studies indicate this cell line is safe, non-tumorigenic and non-immunogenic. HB1.F3.CD NSCs have demonstrated efficacy in animal glioma models. Specific Aim 1 of this research proposal is to determine the safety of intracerebral administration of HB1.F3.CD NSCs in combination with oral 5-FC, in patients with recurrent high-grade gliomas. Specific Aim 2 will assess the extent to which the HB1.F3.CD NSCs convert 5-FC to 5-FU at sites of tumor.
描述(由申请人提供):高级别胶质瘤的弥漫性、浸润性是治愈这些肿瘤的主要障碍。为了对生存产生重大影响,新的治疗策略必须专门针对这些极具侵袭性的肿瘤细胞。人类神经干细胞(NSCs)由于其内在的靶向肿瘤细胞的能力,在神经胶质瘤治疗方面具有巨大的前景。通过利用它们的肿瘤向性和遗传修饰它们以表达治疗性转基因,NSC可以作为靶向抗癌疗法的递送载体。神经干细胞介导的治疗方法可以潜在地增加肿瘤选择性,降低毒性,并实现足以根除侵袭性和残留肿瘤细胞的治疗指数。我们建议使用一个良好的特点,克隆,同种异体NSC线(HB1.F3),已被逆转录病毒转导,稳定表达酶,胞嘧啶脱氨酶(CD),转化为口服前药5-氟胞嘧啶(5-FC)的化疗药物5-氟尿嘧啶(5-FU)。在正常和原位胶质瘤小鼠模型中的初步数据表明,该细胞系是安全的,非致瘤性的,非免疫原性的,并且具有治疗活性。在本研究项目的具体目标1中,将在复发性高级别胶质瘤患者中进行初步可行性研究,以确定脑内给予HB1.F3.CD NSC联合5-FC的安全性。将测试三种剂量水平的NSC。具体目标2将通过评估CD表达NSC在肿瘤部位将5-FC转化为5-FU的程度来证明概念验证。将通过微透析测量5-FC和5-FU的脑内水平,我们将描述5-FC和5-FU的脑内和全身浓度与NSC剂量水平增加之间的关系。19 F MRS还将用于非侵入性记录5-FC治疗期间脑中5-FU的存在。公共卫生相关性:人类胎儿神经干细胞(NSC)具有固有的肿瘤嗜性。当被修饰以表达治疗性转基因时,NSC具有用作抗癌疗法的递送载体的潜力。我们建议临床使用一个良好的特点,克隆,同种异体神经干细胞系,HB1.F3,它已被修改,表达胞嘧啶脱氨酶(CD)。CD将无活性的前药5-氟胞嘧啶(5-FC)转化为有活性的化疗药物5-氟尿嘧啶(5-FU)。初步的生物分布研究表明,该细胞系是安全的,非致瘤性和非免疫原性。HB1.F3.CD NSC已在动物胶质瘤模型中证明了功效。本研究方案的具体目的1是确定复发性高级别胶质瘤患者脑内给予HB1.F3.CD NSC联合口服5-FC的安全性。具体目标2将评估HB1.F3.CD NSC在肿瘤部位将5-FC转化为5-FU的程度。
项目成果
期刊论文数量(0)
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Karen S Aboody其他文献
Karen S Aboody的其他文献
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{{ truncateString('Karen S Aboody', 18)}}的其他基金
Stem Cell/Nanoparticle Constructs for Targeted Ovarian Cancer Therapy
用于卵巢癌靶向治疗的干细胞/纳米颗粒构建体
- 批准号:
9303321 - 财政年份:2015
- 资助金额:
$ 36.52万 - 项目类别:
A Phase I Study of Intracranially Administered Carboxylesterase-Expressing Neural Stem Cells in Combination with Intravenous Irinotecan in Patients with Recurrent High Grade Gliomas
颅内给予表达羧酸酯酶的神经干细胞联合静脉注射伊立替康治疗复发性高级别胶质瘤患者的 I 期研究
- 批准号:
9336834 - 财政年份:2015
- 资助金额:
$ 36.52万 - 项目类别:
Stem Cell/Nanoparticle Constructs for Targeted Ovarian Cancer Therapy
用于卵巢癌靶向治疗的干细胞/纳米颗粒构建体
- 批准号:
9070755 - 财政年份:2015
- 资助金额:
$ 36.52万 - 项目类别:
Phase 1 Study of Neural Stem Cells & 5-FC/Leucovorin for the Treatment of Recurrent High Grade Gliomas
神经干细胞的一期研究
- 批准号:
8753945 - 财政年份:2014
- 资助金额:
$ 36.52万 - 项目类别:
Phase 1 Study of Neural Stem Cells & 5-FC/Leucovorin for the Treatment of Recurrent High Grade Gliomas
神经干细胞的一期研究
- 批准号:
8896311 - 财政年份:2014
- 资助金额:
$ 36.52万 - 项目类别:
Neural Stem Cell Mediated CE-CPT11 Therapy for Neuroblastoma
神经干细胞介导的 CE-CPT11 治疗神经母细胞瘤
- 批准号:
8911385 - 财政年份:2013
- 资助金额:
$ 36.52万 - 项目类别:
Neural Stem Cell Mediated CE-CPT11 Therapy for Neuroblastoma
神经干细胞介导的 CE-CPT11 治疗神经母细胞瘤
- 批准号:
8484289 - 财政年份:2013
- 资助金额:
$ 36.52万 - 项目类别:
Neural Stem Cell Mediated CE-CPT11 Therapy for Neuroblastoma
神经干细胞介导的 CE-CPT11 治疗神经母细胞瘤
- 批准号:
9327077 - 财政年份:2013
- 资助金额:
$ 36.52万 - 项目类别:
Neural Progenitor Cells as Cancer Therapy Vectors
神经祖细胞作为癌症治疗载体
- 批准号:
7913870 - 财政年份:2009
- 资助金额:
$ 36.52万 - 项目类别:
Neural Progenitor Cells as Cancer Therapy Vectors
神经祖细胞作为癌症治疗载体
- 批准号:
7432456 - 财政年份:2005
- 资助金额:
$ 36.52万 - 项目类别:
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