Gene Therapy for Brain Tumors

描述（由申请人提供）：恶性胶质瘤代表人均最昂贵和最病态的单一肿瘤。在先前资助的9年中，该项目已经评估了用于该肿瘤的细胞和HSV溶瘤病毒疗法。在Hochberg博士的领导下，我们仍然专注于这些主题。我们的生产力包括开发前药物激活酶，溶瘤病毒，使用神经前体细胞和独特的分子成像（例如MION）方法进行肿瘤跟踪，这些方法已被合作和高影响力出版物所证明。三个项目和三个核心与Dr. Glorioso的GLP/GMP生产设施合作，作为脑肿瘤联盟（NABTT）的资源，探索胶质母细胞瘤的基因治疗。先前的资金为NGVL/快速试验申请奠定了基础，以支持利用溶瘤病毒MGH2进行的三个I期人体试验。我们继续致力于转化研究，专注于这些生物疗法，包括对溶瘤性HSV耐药性的潜在调节，以及新型成像工具和基因传递方式的开发。项目1 （Chiocca）将确定宿主对溶瘤病毒反应的机制，以及如何调节这种宿主反应以提供更有效的肿瘤杀伤。项目3 （Breakefield/Carter/Sena-Esteves）将专注于通过靶向感染肿瘤细胞并将其与编码治疗蛋白的HSV/AAV扩增载体偶联来增强MGH2治疗。他们还将使用AAV载体；神经前体细胞（npc）和嵌合淋巴细胞，以扩大大脑的治疗领域。项目2 （Weissleder）通过开发可用于成像治疗性NPC和T细胞以及胶质肿瘤中的溶瘤病毒的敏感肽标签，为其他项目提供“胶水”。这些新的成像模式将提供与项目1和项目3中探索的生物疗法的相关性。临床核心B （Krisky/Glorioso）将试点MGH-2和HSV扩增子载体的GLP和GMP生产。MGH2 GMP载体（由NGVL资助）将提供给CTEP进行二期NABTT试验。组织培养，小鼠和分子分析，以及研究和出版物设计由核心A （Finkelstein）的统计监督以及脑肿瘤组织的组织学，分子病理学和免疫细胞化学评估（核心C， Louis）提供支持。该项目旨在回答关于未来脑肿瘤患者基因治疗试验的关键问题的假设。此外，在5年的资助期间，它还提供了一个现实的目标，即为人类试验提供改进的溶瘤性HSV载体范例、靶向T细胞和新型MRI显像剂。

DESCRIPTION (provided by applicant): Malignant gliomas represent the single most costly and morbid neoplasm per capita. During the previously funded nine years, this Program Project has evaluated a pipeline of cellular and HSV oncolytic viral therapies for this tumor. We have remained focused on these themes under Dr. Hochberg. Our productivity includes the development of pro-drug activation enzymes, oncolytic virus, tumor tracking using neural precursor cells and unique molecular imaging (e.g. MION) approaches demonstrated by collaborative and high impact publications. Three Projects and three Cores are united in collaboration with GLP/GMP production facilities of Dr. Glorioso, as a resource for the brain-tumor consortium (NABTT), to explore gene therapy for glioblastomas. Prior funding has set the stage for NGVL/Quick Trial applications in support of three Phase I human trials utilizing the oncolytic virus, MGH2. We continue our commitment to translational research by concentrating upon these biologic therapies, including potential modulation of resistance to oncolytic HSV and the development of novel imaging tools and gene delivery modalities. Project 1 (Chiocca) will determine mechanisms of the host response to the oncolytic virus and how this host response can be modulated to provide more efficient tumor killing. Project 3 (Breakefield/Carter/Sena-Esteves) will focus on enhancing MGH2 therapy by targeting infection to tumor cells and coupling it with HSV/AAV amplicon vectors encoding therapeutic proteins. They will also use AAV vectors; neuroprecursor cells (NPCs) and chimeric lymphocytes to extend the therapeutic field in the brain. Project 2 (Weissleder) provides the 'glue' for other projects by developing sensitive peptide labels which can be used to image therapeutic NPC and T cells, as well as oncolytic viruses in glial tumors. These novel imaging modalities will provide correlations with the biologic therapies explored in Projects 1 and 3. Clinical Core B (Krisky/Glorioso) will pilot the GLP and GMP production of MGH-2 and HSV amplicon vectors. The MGH2 GMP vector (supported by NGVL funding) will be offered to CTEP for Phase II NABTT trials. Tissue culture, murine and molecular analyses, as well as study and publication design are supported by statistical oversight in Core A (Finkelstein), as well as by histologic, molecular pathologic and immunocytochemical evaluations of brain tumor tissue (Core C, Louis). This program aims to answer hypotheses regarding key concerns underlying the conduct of future gene therapy trials for patients afflicted with brain tumors. In addition it offers, during five years of funding, the realistic goal of provision to human trials of improved oncolytic HSV vectors paradigms, targeted T cells and novel MRI imaging agents.