Gene Therapy for Brain Tumors

描述(由申请人提供)：恶性胶质瘤是人均最昂贵和最病态的肿瘤。在之前资助的九年中，该计划项目评估了一系列细胞和HSV溶瘤病毒治疗该肿瘤的流水线。在霍奇伯格博士的领导下，我们一直专注于这些主题。我们的生产力包括开发前药物激活酶、溶瘤病毒、使用神经前体细胞跟踪肿瘤以及合作和高影响力出版物所展示的独特分子成像方法(例如Mion)。三个项目和三个核心与Glorioso博士的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。先前的资金已经为NGVL/快速试验应用奠定了基础，以支持利用溶瘤病毒MGH2进行的三个第一阶段人体试验。我们继续致力于转译研究，专注于这些生物疗法，包括对溶瘤单纯疱疹病毒耐药性的潜在调节，以及开发新的成像工具和基因输送方式。项目1(Chiocca)将确定宿主对溶瘤病毒的反应机制，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)将专注于通过靶向肿瘤细胞感染并将其与编码治疗性蛋白的HSV/AAV扩增载体偶联来加强MGH2的治疗。他们还将使用AAV载体、神经前体细胞(NPC)和嵌合淋巴细胞来扩大大脑的治疗领域。项目2(Weissleder)通过开发可用于对治疗性鼻咽癌和T细胞以及胶质瘤中的溶瘤病毒进行成像的敏感多肽标记，为其他项目提供了粘合剂。这些新的成像模式将提供与项目1和3中探索的生物疗法的相关性。临床核心B(KRisk/Glorioso)将试验生产MGH-2和HSV扩增载体的GLP和GMP。MGH2 GMP载体(由NGVL资金支持)将提供给CTEP进行NABTT第二阶段试验。组织培养、小鼠和分子分析以及研究和出版物设计得到了核心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)的支持。该计划旨在回答有关未来对脑瘤患者进行基因治疗试验的关键问题的假设。此外，在五年的资助期间，它提供了一个现实的目标，即向人类试验提供改进的溶瘤单纯疱疹病毒载体范例、靶向T细胞和新型核磁共振成像试剂。

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.