Genetically-Modified Neural Stem Cell Based Virotherapy for Invasive Gliomas

基于基因修饰的神经干细胞的病毒疗法治疗侵袭性胶质瘤

• 批准号: 9262538
• 负责人: Atique U. Ahmed
• 金额: $ 17.6万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262538
• 关键词: Genetically; Modified; Neural; Stem; Cell

Project Summary: Glioblastoma multiforme is a primary malignancy of the central nervous system that is nearly universally fatal due to the disseminated nature of these tumors. In this context, our lab and others have investigated unique tumor-tropic properties of neural stem cells (NSCs) as a novel platform for targeted delivery of anti-cancer agents in the brain. However, despite the strong tumor tropism exhibited by NSCs, only a small portion of the transplanted cells is able to migrate towards the tumor. This poor tumor homing efficiency is one of the limiting factors for NSC-based anti-cancer therapeutic approach and must be address. On this basis, I now propose to study the underlying molecular mechanisms of the inherent tumor-tropic properties of NSCs, which will allow us to develop protocol to further improve the tumor homing efficiency of NSCs. Our preliminary data indicated that migratory subpopulation of NSCs differs significantly from their nonmigratory counterpart based on the level of VEGFR2 and nestin expression. Moreover, blocking VEGFR2/VEGF signaling significantly impaired tumor-tropic migratory properties of NSCs. Thus, further detail understanding of signaling pathways that regulate migratory properties of NSCs will be crucial for development of optimized NSC-based targeted therapy (Aim 1). In addition, the reported immunosuppressive properties of NSCs are a very attractive attribute to their utilization as a cell carrier for novel anti-glioma therapy given that they will allow therapeutic payloads such as oncolytic viruses to be shielded from the host immune response. Therefore, I now propose to characterize the molecular nature of NSC-mediated immunosuppressant in the context of viral infection and examine how it may help to enhance therapeutic efficacy of anti-glioma oncolytic virotherapy (Aim 2). And finally, our preliminary data show that the viability of NSCs is significantly compromised upon ex vivo loading with the oncolytic virus due to replication-mediated carrier cell lysis. This is an essential step for the tumor-specific amplification of the therapeutic viruses, but counter-intuitive for long-term survival and tumor-specific homing of the carrier cells. Based on this, I hypothesize that blocking viral replication transiently during ex vivo loading will enhance the survival, loading capacity and tropism of NSCs for gliomas. In our final specific aim, I now propose to develop an inducible system that will allow us to maximize the ex vivo loading of the oncolytic virus without altering the survival and tropism of the NSCs (Aim 3). In conclusion, the proposed studies have the potential to making an impact beyond neuro-oncology and will accelerate the translational of the stem cell-based therapy in the clinic.

项目概要： 多形性胶质母细胞瘤是中枢神经系统的原发性恶性肿瘤， 由于这些肿瘤的扩散性质，通常是致命的。在这种背景下，我们的实验室和其他实验室 已经研究了神经干细胞（NSC）作为一种新的平台的独特的肿瘤嗜性特性， 在大脑中靶向递送抗癌剂。然而，尽管具有很强的肿瘤向性， 由于NSC表现出的这些特性，只有一小部分移植的细胞能够向NSC迁移。 肿瘤这种较差的肿瘤归巢效率是基于神经干细胞的抗癌的限制因素之一 治疗方法和必须解决。在此基础上，我建议研究 神经干细胞固有的亲肿瘤特性的潜在分子机制， 将使我们能够开发出进一步提高神经干细胞肿瘤归巢效率的方案。 我们的初步数据表明，神经干细胞的迁移亚群与其 基于VEGFR 2和巢蛋白表达水平的非迁移对应物。此外，阻挡 VEGFR 2/VEGF信号转导显著损害了NSC的向肿瘤迁移特性。因此，在本发明中， 进一步详细了解调节神经干细胞迁移特性的信号通路， 这对于开发优化的基于神经干细胞的靶向治疗至关重要（目标1）。此外，据报道， 神经干细胞的免疫抑制特性是其作为免疫抑制剂的用途的一个非常有吸引力的属性。 考虑到它们将允许治疗有效载荷， 作为溶瘤病毒以免受宿主免疫反应的影响。因此，我现在提议 在病毒感染的背景下表征NSC介导的免疫抑制剂的分子性质， 感染，并检查它如何有助于提高抗胶质瘤溶瘤剂的治疗效果 病毒疗法（目的2）。最后，我们的初步数据表明，神经干细胞的活力显着 由于复制介导的载体细胞， 溶解这是治疗性病毒的肿瘤特异性扩增的必要步骤，但 这对于载体细胞的长期存活和肿瘤特异性归巢是违反直觉的。在此基础上， 我假设，在体外加载过程中短暂阻断病毒复制将增强 神经干细胞对胶质瘤的存活、负载能力和嗜性。在我们最后的具体目标，我现在 我建议开发一种诱导系统，使我们能够最大限度地提高体外加载的 溶瘤病毒而不改变NSC的存活和向性（目的3）。最后 拟议的研究有可能产生超出神经肿瘤学的影响， 加速干细胞治疗在临床上的转化。

项目成果

Stem Cell-Based Cell Carrier for Targeted Oncolytic Virotherapy: Translational Opportunity and Open Questions.

• DOI: 10.3390/v7122921
• 发表时间: 2015-11-27
• 期刊: Viruses
• 作者: Kim J;Hall RR;Lesniak MS;Ahmed AU
• 通讯作者: Ahmed AU