Neural Stem Cell Based Virotherapy for Malignant Glioma

基于神经干细胞的恶性胶质瘤病毒疗法

• 批准号: 8737319
• 负责人: Bakhtiar Yamini
• 金额: $ 115.15万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737319
• 关键词: Adenovirus Vector; Adenoviruses; Animal Model; Biodistribution; Clinical; Clinical Trials; Cyclic GMP; Disease; Disease Outcome; Engraftment; Glioma; Goals; Healthcare; Human; Immune response; In Vitro; Injection of therapeutic agent; Investigational Drugs; Investigational New Drug Application; Magnetic Resonance Imaging; Malignant Glioma; Malignant neoplasm of brain; Mediating; Modification; Monitor; National Institute of Neurological Disorders and Stroke; Oncolytic; Phase I Clinical Trials; Preparation; Public Health; Radiation therapy; Research Design; Safety; Secure; Specificity; Stem cells; Toxicology; Translating; Translational Research; Treatment Efficacy; United States Food and Drug Administration; Viral; Virotherapy; Virus; Work; base; chemotherapy; clinical lot; conditionally replicative adenovirus; improved; meetings; migration; nerve stem cell; novel; novel strategies; programs; public health relevance; response; survivin; temozolomide; tumor

DESCRIPTION (provided by applicant): The major aim of this U01 (NINDS Cooperative Program in Translation Research) application is to develop a highly novel approach for the treatment of malignant brain tumors. Our strategy entails the use of neural stem cells (NSC) as carriers of an oncolytic adenovirus which directly targets glioma stem cells. Since one of the major limitations of virotherapy is poor spread following injection, we have recently shown that NSCs can more effectively migrate and deliver an oncolytic adenovirus to intracranial glioma than local injection of the virus alone. This form of carrier mediated delivery leads to enhanced viral replication in the tumor, decreased anti-adenoviral immune response, and a much more potent anti-tumor response than local injection of the virus alone. In order to translate our work into the clinical setting, we have held a pre-IND meeting with the Food and Drug Administration (FDA). We have completed some of the preliminary FDA directed studies, and now propose to develop a clinical trial in which a novel oncolytic adenovirus will be delivered via NSCs. We hypothesize that an adenoviral vector targeted to GBM, when rendered selectively replicative via transcriptional/transductional modification and delivered via NSCs, will demonstrate superior specificity required for human clinical trials and thereby allow full realization of the potential benefits of virotherapy for malignant glioma. To achieve this goal, we would like to utilize the U01 mechanism to complete the following specific aims which will ultimately culminate in securing an IND for a phase I clinical trial: Milestone/Aim 1: Validate the therapeutic efficacy of CRAd-Survivin-pk7 loaded NSCs in vitro and in animal models of glioma. Milestone/Aim 2: Evaluate the therapeutic efficacy and safety monitoring with CRAd-Survivin-pk7 loaded NSCs in the presence of temozolomide-based chemotherapy and radiotherapy. Milestone/Aim 3: Determine the migration, engraftment, and long-term fate of CRAd-Survivin-pk7 loaded NSCs in vitro and in animal models of glioma with MRI. Milestone/Aim 4: Perform a toxicology and biodistribution study with NSC-loaded cGMP-grade clinical lot virus. Milestone/Aim 5: Conduct RAC and FDA preparation meetings and assemble documents for filing Investigational New Drug (IND) application for neural stem cell based virotherapy in malignant glioma.

描述（由申请人提供）：该U01的主要目的（翻译研究中的NINDS合作计划）的应用是开发一种高度新颖的方法来治疗恶性脑肿瘤。我们的策略需要将神经干细胞（NSC）用作直接靶向神经胶质瘤干细胞的癌腺病毒的载体。由于注射后病毒疗法的主要局限性之一是扩散较差，因此我们最近表明，与单独的病毒相比，NSC可以更有效地迁移并将肿瘤性腺病毒向颅内神经胶质瘤传递到颅内神经胶质瘤。这种形式的载体介导的递送导致肿瘤中的病毒复制增强，抗腺病毒免疫反应降低，并且比仅局部注射病毒的抗腺病毒反应降低了。为了将我们的工作转化为临床环境，我们与食品药品监督管理局（FDA）举行了预先会议。我们已经完成了一些初步的FDA定向研究，现在建议开发一项临床试验，在该试验中，将通过NSC进行新的溶瘤腺病毒。我们假设一个针对GBM的腺病毒载体通过转录/转导性修饰和通过NSC进行选择性复制性时，将证明人类临床试验所需的较高特异性，从而可以完全实现病毒疗法对恶性肿瘤的潜在益处。为了实现这一目标，我们希望利用U01机制来完成以下特定目标，这些特定目标最终将最终确保I阶段I临床试验的IND：里程碑/目标1：验证Crad-Survivin-PK7在体外和Gliomoma动物模型中加载NSC的Crad-Survivin-PK7的治疗功效。里程碑/AIM 2：在存在基于替莫唑胺的化学疗法和放疗的情况下，使用Crad-Survivin-PK7加载NSC的治疗功效和安全性监测。里程碑/目标3：确定Crad-Survivin-PK7的迁移，植入和长期命运在体外和MRI的神经胶质瘤动物模型中加载NSC。里程碑/目标4：使用NSC负载的CGMP级临床批次病毒进行毒理学和生物分布研究。里程碑/目标5：进行RAC和FDA准备会议和组装文件，以申请研究新药（IND）在恶性神经胶质瘤中基于神经干细胞的病毒疗法申请。

项目成果

Nanoparticle-programmed self-destructive neural stem cells for glioblastoma targeting and therapy.

• DOI: 10.1002/smll.201301111
• 发表时间: 2013-12-20
• 期刊: SMALL
• 影响因子: 13.3
• 作者: Cheng, Yu;Morshed, Ramin;Cheng, Shih-Hsun;Tobias, Alex;Auffinger, Brenda;Wainwright, Derek A.;Zhang, Lingjiao;Yunis, Catherine;Han, Yu;Chen, Chin-Tu;Lo, Leu-Wei;Aboody, Karen S.;Ahmed, Atique U.;Lesniak, Maciej S.
• 通讯作者: Lesniak, Maciej S.

Blood-brain barrier permeable gold nanoparticles: an efficient delivery platform for enhanced malignant glioma therapy and imaging.

• DOI: 10.1002/smll.201400654
• 发表时间: 2014-12-29
• 期刊: SMALL
• 影响因子: 13.3
• 作者: Cheng, Yu;Dai, Qing;Morshed, Ramin A.;Fan, Xiaobing;Wegscheid, Michelle L.;Wainwright, Derek A.;Han, Yu;Zhang, Lingjiao;Auffinger, Brenda;Tobias, Alex L.;Rincon, Esther;Thaci, Bart;Ahmed, Atique U.;Warnke, Peter C.;He, Chuan;Lesniak, Maciej S.
• 通讯作者: Lesniak, Maciej S.

Analysis of glioblastoma tumor coverage by oncolytic virus-loaded neural stem cells using MRI-based tracking and histological reconstruction.

• DOI: 10.1038/cgt.2014.72
• 发表时间: 2015-01
• 期刊: Cancer gene therapy
• 影响因子: 6.4

Neural stem cell-mediated delivery of oncolytic adenovirus.

神经干细胞介导的溶瘤腺病毒递送。

• DOI: 10.1002/0471142905.hg1311s85
• 发表时间: 2015
• 期刊: Current protocols in human genetics
• 作者: Kim,JuliusW;Kane,JRobert;Young,JacobS;Chang,AlanL;Kanojia,Deepak;Qian,Shuo;Spencer,DrewA;Ahmed,AtiqueU;Lesniak,MaciejS
• 通讯作者: Lesniak,MaciejS

Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma.

• DOI: 10.1016/j.biomaterials.2013.10.064
• 发表时间: 2014-01
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Chung, Eun Ji;Cheng, Yu;Morshed, Ramin;Nord, Kathryn;Han, Yu;Wegscheid, Michelle L.;Auffinger, Brenda;Wainwright, Derek A.;Lesniak, Maciej S.;Tirrell, Matthew V.
• 通讯作者: Tirrell, Matthew V.