Enhanced GBM Therapy Using a New Class of HSV Oncolytic Vector

使用新型 HSV 溶瘤载体增强 GBM 治疗

基本信息

批准号：
8775633
负责人：
Paola Grandi
金额：
$ 31.6万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8775633
关键词：
Address Attenuated Binding Brain Brain Neoplasms CSPG4 gene Cell surface Cells Characteristics Classification Clinical Trials Complement Cytoskeleton Data Detection Effectiveness Engineering Ensure Environment Epitopes Exhibits Extracellular Matrix Extracellular Matrix Degradation Feasibility Studies Generations Genes Glioblastoma Glioma Glycoproteins Growth HSV vector Health Heparitin Sulfate Herpes Simplex Infections Human Human Characteristics Immunocompetent In complete remission Infection Ligands Lytic Magnetic Resonance Imaging Malignant - descriptor Measures Mediating Metalloproteases MicroRNAs Modeling Modification Mus Mutagenesis Mutation Natural Immunity Neoplasm Metastasis Neurons Normal Cell Normal tissue morphology Nude Mice Oncolytic Oxygen measurement, partial pressure, arterial Patients Penetration Peptides Performance Phase Pre-Clinical Model Recurrence Repression Safety Simplexvirus Site Specific qualifier value Specificity Staging Technology Testing Tissues Toxic effect Toxicology Transgenes Translations Treatment Efficacy Tumor Cell Invasion Tumor Stem Cells Viral Viral Genes Viral Physiology Viral Vector Virion Virus Virus Replication Wit Xenograft procedure alternative treatment arm attenuation base brain cell cell growth cell killing cell motility design differential expression effective therapy efficacy testing epidermal growth factor receptor VIII implantation improved in vitro Model in vivo innovation lytic replication meetings migration mouse model neoplastic cell nerve stem cell neurovirulence next generation novel oncolysis oncolytic vector permissiveness preclinical study prototype receptor tumor tumor specificity vector vector control virus envelope

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is a deadly brain tumor without effective therapy. Oncolytic herpes simplex viral vectors (OVs) provide an attractive treatment alternative based on preclinical studies however clinical trials have thus far been disappointing showing only anecdotal evidence for complete responses. We propose vector design strategies to overcome impediments to robust vector performance. Important vector limitations include (i) inadequate intra-tumoral virus growth due to the introduction of attenuating mutations (ii) reduced vector distribution due to poor initial penetration of the tumor mass and limited spread of new virions, and (iii) tumor cell migration away from the tumor margin, limiting their accessibility to infectious virus. To meet these challenges, we propose to create an innovative oHSV that retains the full complement of HSV replication functions that will ensure optimal vector replication and lytic activity. Vector safety will be ensured by vector targeting to tumor-related receptors including tumor stem cell markers and the expression of essential virus genes will be controlled by naturally occurring micro-RNAs (miRs) that are differentially expressed in normal brain and tumor cells. In addition, the vector will be armed wit human matrix metalloproteases (MMPs) that impair formation of the extracellular matrix (ECM), a natural barrier to virus spread, and with an antagonist of c-Met activation, an essential functio for tumor cell growth and migration. Together these transgenes are expected to enhance intra-tumoral vector spread, increase tumor access of infectious virus and impede tumor cell migration. The safety of these vectors will be evaluated in toxicology studies using immunocompetent mice, and treatment efficacy will be examined in orthotopic mouse models involving intracranial implantation of primary human glioblastoma initiating cells (GICs) that represent the four classes of stage IV GBM. The xenografts exhibit characteristics of human glioblastoma including tumor cell migration and provide a means to evaluate the utility of this next generation of oHSV as an effective tumor therapy. We anticipate that this combination of tumor targeting, robust vector replication and enhanced vector access to tumor cells will provide a powerful technology to eradicate tumors with the potential for translation to patients.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是一种致命的脑肿瘤，没有有效的治疗方法。根据临床前研究，溶瘤单纯疱疹病毒载体（OV）提供了一种有吸引力的治疗替代方案，但迄今为止的临床试验表明令人失望的是，仅显示完整反应的轶事证据。我们提出矢量设计策略来克服稳健矢量性能的障碍。重要的载体限制包括（i）由于引入减毒突变而导致肿瘤内病毒生长不足（ii）由于肿瘤的初始渗透性差而减少载体分布新病毒体的大量传播和有限的传播，以及（iii）肿瘤细胞迁移远离肿瘤边缘，限制了它们接触传染性病毒的机会。为了应对这些挑战，我们建议创建一种创新的 oHSV，它保留了完整的 HSV 复制功能，以确保最佳的载体复制和裂解活性。载体的安全性将通过靶向肿瘤相关受体（包括肿瘤干细胞标记物）的载体来确保，并且基本病毒基因的表达将由在正常脑和肿瘤细胞中差异表达的天然存在的微RNA（miR）控制。此外，该载体将配备人基质金属蛋白酶（MMP），该酶会损害细胞外基质（ECM）（病毒传播的天然屏障）的形成，并配备c-Met激活的拮抗剂（肿瘤细胞生长的重要功能）和迁移。这些转基因预计将增强肿瘤内载体的传播，增加感染性病毒进入肿瘤的机会并阻止肿瘤细胞迁移。这些载体的安全性将在毒理学研究中使用免疫活性小鼠进行评估，治疗效果将在原位小鼠模型中进行检查，该模型涉及颅内植入原代人胶质母细胞瘤起始细胞（GIC），这些细胞代表四类 IV 期 GBM。异种移植物表现出人类胶质母细胞瘤的特征，包括肿瘤细胞迁移，并提供了一种评估下一代 oHSV 作为有效肿瘤疗法的实用性的方法。我们预计，肿瘤靶向、强大的载体复制和增强的载体对肿瘤细胞的访问的结合将提供一种强大的技术来根除肿瘤，并有可能转化为患者。