Brain Tumor Stem Cell-targeted Gene Therapy
脑肿瘤干细胞靶向基因治疗
基本信息
- 批准号:7221638
- 负责人:
- 金额:$ 16.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-09-28 至 2007-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Glioblastoma Multiforme (GBM) is a lethal brain tumor that typically causes death within 2 years after initial diagnosis. GBM accounts for 25% of all primary brain tumors in adults. Despite improvements in precise surgical de-bulking, radiation, and drug therapy, the prognosis for GBM patients has not significantly changed in decades. Novel therapies are therefore desperately needed. Recent studies have revealed that similar to leukemia, a glioma is a heterogeneous tumor comprised of differentiated tumor cells and cancerous progenitor cells known as "brain tumor stem cells" (BTSCs). It has been demonstrated that BTSCs account for a minor fraction of total tumor cells, but are the only cells within the tumor mass that are capable of tumor renewal and tumor recurrence. These findings have significance because they suggest that novel therapy should be designed to selectively target BTSC, rather than conventional approaches that target the bulk tumor mass. We have discovered the BTSCs may be invisible to the immune system because they lack expression of cell surface receptors needed for both innate and adaptive immune-mediated killing. Treatment of BTSCs with interferon gamma (INF-y) restores their immunogenicity and susceptibility to being killed. We are moving forward with our Sleeping Beauty (SB) Transposon plasmid-based gene transfer system for treatment of brain tumors with INF-y gene therapy. In contrast to conventional plasmid DNA vectors, SB mediates sustained gene expression in glioma cells and therefore has potent anti-tumor efficacy. In parallel, we will develop and test a novel BTSC-targeted plasmid delivery vector by conjugating polyethylenimine (PEI) transfection reagent with anti-CD133 antibody because BTSCs express the CD133 receptor but their daughter cells do not. PEI/DNA/CD133mAb complexes will be used to deliver a potent suicide gene into an improved, invasively growing mouse model of GBM alone, or in combination with SB-mediated INF-y gene therapy. We contend that the combination of BTSC-targeted cell death with sustained INF-y mediated immune stimulation will provide a breakthrough in brain tumor immunotherapy by evoking an immune response that eliminates residual BTSCs. This project will initiate the commercialization of these 2 drugs for GBM therapy. In Aim1, we will develop and optimize BTSC-targeted gene delivery by perfecting PEI/DNA/CD133mAb complexes. These experiments will be done in vitro using human GBM tumor samples to produce a targeted drug for a phase I clinical trial. In Aim 2, the efficacy of SB-mediated INF-y gene therapy and BTSC-targeted suicide gene therapy will be evaluated in vivo in preparation for large animal studies and eventual IND application. Completion of these studies is crucial to accelerate commercialization of SB and BTSC-targeted gene therapy vectors, in order to meet our goal of providing safe and effective gene therapy for treatment of patients with fatal brain tumors. There is currently no effective therapy for patients with glioblastoma, a lethal brain tumor that accounts for 25% of primary brain tumors in adults. Most patients die within 2 years after diagnosis and over 10, 000 people die each year from glioblastoma in the United States alone. In this project, we will develop and begin to commercialize a novel form of gene therapy that is intended to destroy rare "tumor stem cells", which are the cells that ultimately kill glioblastoma patients.
描述(申请人提供):多形性胶质母细胞瘤(GBM)是一种致命的脑肿瘤,通常在最初诊断后2年内死亡。在成人所有的原发脑瘤中,基底节瘤占25%。尽管在精确的外科治疗、放射治疗和药物治疗方面有所改善,但几十年来,GBM患者的预后并没有显著改变。因此,迫切需要新的治疗方法。最近的研究表明,胶质瘤类似于白血病,是一种由分化的肿瘤细胞和被称为脑肿瘤干细胞(BTSCs)的癌祖细胞组成的异质性肿瘤。已有研究表明,BTSCs只占肿瘤细胞总数的一小部分,但它是肿瘤内唯一具有肿瘤再生和肿瘤复发能力的细胞。这些发现具有重要意义,因为它们表明,新的治疗方法应该被设计成选择性地针对BTSC,而不是传统的针对大块肿瘤的方法。我们已经发现,BTSC可能对免疫系统是看不见的,因为它们缺乏天然和获得性免疫介导的杀伤所需的细胞表面受体的表达。用干扰素-γ(INF-y)治疗BTSCs可以恢复其免疫原性和被杀伤的敏感性。我们正在推进我们的睡美人(SB)转座子转座子基因转移系统,用于使用INF-y基因治疗脑肿瘤。与传统的质粒DNA载体相比,SB介导了胶质瘤细胞中持续的基因表达,因此具有强大的抗肿瘤效果。同时,我们将通过将聚乙烯亚胺(PEI)转染剂与抗CD133抗体偶联来开发和测试一种新型的BTSC靶向载体,因为BTSC表达CD133受体,而它们的子细胞不表达CD133受体。PEI/DNA/CD133mAb复合体将被用来单独或与SB介导的INF-y基因治疗相结合,将有效的自杀基因输送到改良的、侵袭性生长的GBM小鼠模型中。我们认为,BTSC靶向细胞死亡与持续的INF-y介导的免疫刺激相结合,将通过激发免疫反应来消除残留的BTSC,从而为脑肿瘤免疫治疗提供突破。该项目将启动这两种治疗基底膜的药物的商业化进程。在Aim1中,我们将通过完善PEI/DNA/CD133mAb复合体来开发和优化BTSC靶向基因传递。这些实验将在体外使用人的GBM肿瘤样本来生产一种靶向药物,用于I期临床试验。在目标2中,将在体内评估SB介导的INF-y基因治疗和BTSC靶向自杀基因治疗的疗效,为大型动物研究和最终的IND应用做准备。这些研究的完成对于加速SB和BTSC靶向基因治疗载体的商业化至关重要,以实现我们为致命脑瘤患者提供安全有效的基因治疗的目标。胶质母细胞瘤是一种致命的脑瘤,占成人原发脑瘤的25%,目前还没有有效的治疗方法。大多数患者在确诊后两年内死亡,仅在美国每年就有超过10,000人死于胶质母细胞瘤。在这个项目中,我们将开发一种新的基因疗法,并开始将其商业化,这种疗法旨在摧毁罕见的“肿瘤干细胞”,这些细胞最终会杀死胶质母细胞瘤患者。
项目成果
期刊论文数量(0)
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John R Ohlfest其他文献
John R Ohlfest的其他文献
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{{ truncateString('John R Ohlfest', 18)}}的其他基金
Discovery and Validation of Tumor Immunoevasion Mechanisms
肿瘤免疫逃避机制的发现和验证
- 批准号:
8166119 - 财政年份:2011
- 资助金额:
$ 16.36万 - 项目类别:
Understanding and enhancing mechanisms of priming in cancer immunotherapy
了解和增强癌症免疫治疗的启动机制
- 批准号:
8305867 - 财政年份:2010
- 资助金额:
$ 16.36万 - 项目类别:
Understanding and enhancing mechanisms of priming in cancer immunotherapy
了解和增强癌症免疫治疗的启动机制
- 批准号:
7953371 - 财政年份:2010
- 资助金额:
$ 16.36万 - 项目类别:
Concurrent Immune Stimulation and Inhibition of Angiogenesis for Glioma Therapy
神经胶质瘤治疗中同时免疫刺激和血管生成抑制
- 批准号:
7384288 - 财政年份:2007
- 资助金额:
$ 16.36万 - 项目类别:
Concurrent Immune Stimulation and Inhibition of Angiogenesis for Glioma Therapy
神经胶质瘤治疗中同时免疫刺激和血管生成抑制
- 批准号:
7490563 - 财政年份:2007
- 资助金额:
$ 16.36万 - 项目类别:
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