Vector delivery to modify the brain tumor and its microenvironment

胶质母细胞瘤（GBM）是最常见的原发性脑癌。尽管进行了积极 尽管目前的治疗包括手术、放疗和化疗，但复发性疾病几乎总是致命的。 溶瘤HSV载体（例如G207）在GBM的治疗中显示出一些前景，然而， 几乎没有完整的反应，令人失望的结果很可能与载体不足有关。 感染和生长，特别是在从肿瘤块迁移并侵入的肿瘤细胞中 正常的脑组织因此，项目3的中心目标是改善溶瘤载体的递送、复制和表达。 并在保持安全性和肿瘤特异性的同时扩散。因为肿瘤微环境的变化 极大地影响病毒生长，我们建议进一步用 改善载体分布、克服局部抗病毒反应和增强易感性的基因 凋亡机制。具体而言，我们建议：（一）探索生长，扩散和抗肿瘤 删除非必需的HSV-1高活性毒株科斯溶瘤载体（KOV）的潜力 立即早期（即）基因ICPO、ICP 22和ICP 47，（ii）使用重组KOV载体 表达具有强抗血管生成活性的分泌型基质金属蛋白酶蛋白酶（ADAMTS-8）， 为了增加初始载体分布和促进复制期间载体传播， (iii)检查能够表达VH 1、bin 1和显性阴性的重组KOV的用途 IKB（kBaM）作为干扰素γ（IFN γ）和吲哚胺2，3-双加氧酶（IDO）抗病毒的抑制剂 和细胞因子诱导途径，以及（iv）评估重组KOV表达的能力， (a)阻断其抗凋亡功能的新型显性负性PKCe（DNP），（B）半胱天冬酶8a， 启动凋亡级联反应和（c）优化的重组可溶性TRAIL（orsTRAIL）以诱导 肿瘤细胞凋亡最终，我们的目的是创造一种强大的溶瘤载体， 这些组合的生长促进，抗肿瘤功能，将为这种形式的新标准， 神经胶质瘤治疗将这种新载体与G207进行比较，以证明其改善的抗肿瘤活性。 应答高度工程化的载体也将为更好地了解胶质瘤提供机会 细胞生物学，大大提高抗癌药物的使用与项目1合作，并协助 与项目2合作诱导肿瘤特异性免疫。我们的复制能力 基因载体应该在有效的多模式治疗的发展中是有用的，这是一个重要的 我们的计划项目赠款的总体目标。

Glioblastoma mutliforme (GBM) is the most common form of primary brain cancer. Despite aggressive therapies including surgery, radiotherapy, and chemotherapy, recurrent disease is nearly always fatal. Oncolytic HSV vectors (e.g. G207) have shown some promise in the treatment of GBM however there have been few complete responses, a disappointing outcome most likely related to inadequate vector infection and growth, particularly among tumor cells that migrate from the tumor mass and invade normal brain tissue. Thus a central goal of Project 3 is to improve oncolytic vector delivery, replication and spread while maintaining safety and tumor specificity. Because changes in the tumor microenvironment greatly influence virus growth, we propose further to arm these oncolytic vectors with genes that improve vector distribution, overcome local anti-viral responses and enhance susceptibility to apoptotic mechanisms. Specifically, we propose to: (i) to explore the growth, spread and anti-tumor potential of a highly active HSV -1 strain KOS Oncolytic Vector (KOV) deleted for the non-essential immediate early (I.E.) genes ICPO, ICP22 and ICP47, (ii) to employ a recombinant KOV vector expressing a secreted matrix metalloproteinase protease (ADAMTS-8) with strong anti-angiogenic activity in an effort to increase initial vector distribution and to facilitate vector spread during replication, (iii) examine the use of a recombinant KOV capable of expressing VH1, binl and a dominant negative IKB (kBaM) as inhibitors of the interferon gamma (IFNy) and indoleamine 2,3-dioxygenase (IDO) antiviral and cytokine induction pathways and (iv) to evaluate the ability of recombinant KOV expressing (a) a novel dominant negative PKCe (DNP) that blocks its anti-apoptotic function, (b) caspase 8a to launch the apoptotic cascade and (c) an optimized recombinant soluble TRAIL (orsTRAIL) to induce tumor cell apoptosis. Ultimately, it is our intention to create a powerful oncolytic vector that exploits these combined growth-facilitating, anti-tumor functions that will set a new standard for this form of glioma therapy. This new vector will be compared to G207 to demonstrate improved anti-tumor responses. The highly engineered vector will also provide opportunities to better understand glioma cell biology, greatly improve the use of anti-cancer drugs in collaboration with Project 1 and assist the induction of tumor-specific immunity in collaboration with Project 2. Together our replication competent gene vectors should be useful in the development of an effective multi-modal therapy, an important overall goal of our program project grant.