Gene Therapy for Brain Tumors

恶性神经胶质瘤是人均最昂贵和最病态的肿瘤。期间 该计划项目已经评估了一个细胞和HSV溶瘤药物的管道， 病毒疗法来治疗这种肿瘤我们在霍克伯格博士的领导下一直专注于这些主题。我们 生产力包括开发前药活化酶，溶瘤病毒，使用 神经前体细胞和独特的分子成像（如MION）方法，通过合作证明 和高影响力的出版物。三大工程、三大核心与GLP/GMP合作， Glorioso博士的生产设施，作为脑肿瘤联盟（NABTT）的资源，探索基因 胶质母细胞瘤的治疗。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的三个I期人体试验。我们继续致力于翻译 通过集中研究这些生物疗法，包括对耐药性的潜在调节， 溶瘤HSV和新的成像工具和基因递送方式的发展。项目1 （Chiocca）将确定宿主对溶瘤病毒的反应机制以及这种宿主反应如何 可以被调节以提供更有效的肿瘤杀伤。项目3（布雷克菲尔德/卡特/塞纳-埃斯特韦斯）将 专注于通过靶向感染肿瘤细胞并将其与HSV/AAV偶联来增强MGH2治疗 编码治疗性蛋白质的扩增子载体。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展脑中的治疗领域。项目2（Weissleder） 通过开发可用于成像的敏感肽标签， 治疗性NPC和T细胞，以及神经胶质肿瘤中的溶瘤病毒。这些新的成像方式将 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 （Krisky/Glorioso）将试验MGH-2和HSV扩增子载体的GLP和GMP生产。MGH2 GMP载体（由NGVL资金支持）将提供给CTEP用于II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得到统计学的支持， 核心A（Finkelstein）的疏忽，以及组织学，分子病理学和免疫细胞化学 脑肿瘤组织的评价（Core C，Louis）。该计划旨在回答有关关键假设 对未来进行脑肿瘤患者基因治疗试验的担忧。在 此外，它提供了，在五年的资金，现实的目标，提供人体试验的改善， 溶瘤HSV载体范例、靶向T细胞和新型MRI成像剂。

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 evalutions 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.