Optimizing oncolytic virus therapy for glioblastoma

优化胶质母细胞瘤的溶瘤病毒治疗

• 批准号: 10618742
• 负责人: Balveen Kaur
• 金额: $ 38.5万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618742
• 关键词: Adult Glioblastoma; Angiogenesis Inhibitors; Biodistribution; Biological Response Modifier Therapy; Brain; Brain Neoplasms; Cells; Decision Trees; Excision; FDA approved; Future; G207; Genes; Glioblastoma; Glioma; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Herpesvirus 1; Immunocompetent; In Vitro; Intracranial Neoplasms; Laboratories; Lead; Lipids; Lytic; Malignant Neoplasms; Metastatic Melanoma; Mitochondria; Mus; Oncolytic; Oncolytic viruses; PTEN gene; Patients; Phase; Phosphoric Monoester Hydrolases; Pre-Clinical Model; Production; Prognosis; Proteins; Public Health; Reading Frames; Reporting; Resistance; Safety; Simplexvirus; Structure; Testing; Therapeutic; Toxic effect; Transgenes; Treatment Efficacy; Vertebral column; Viral; Virus; anti-tumor immune response; antitumor effect; attenuation; clinical development; cytotoxicity; extracellular; improved; in vivo; melanoma; neoplastic cell; neurovirulence; novel; novel strategies; novel therapeutics; oncolytic virotherapy; prototype; reconstitution; therapeutic development; therapeutic evaluation; therapeutic transgene; tumor; tumorigenic; vector; virus development

ABSTRACT The overarching goal of this project is to identify a new lead oncolytic virus for the treatment of adult glioblastoma (GBM). Oncolytic viral (OV) therapy is a promising biological therapy that preferentially targets tumor cells for lytic destruction [1, 2]. Oncolytic HSV-1 (oHSV) derived virus that encodes for GM-CSF (IMLYGIC®) has been recently approved for non-ressectable metastatic melanoma [3, 4]. In our past endeavors, we have created and tested the therapeutic efficacy of oHSV armed with therapeutic transgenes. These viruses have been created in rHSVQ1 (HSVQ): an HSV virus backbone that is deleted for both copies of the viral neuro- virulence gene ICP34.5 and it contains a gene disrupting insertion in viral ICP6. This backbone has attenuations identical to G207, a virus that has been tested and found to be safe in patients with GBM after intracranial inoculation into the tumor or when given into the post resection tumor cavity [5, 7-10]. Here we will create a novel dually armed oncolytic virus (that encode for therapeutic transgenes: Vstat120, PTENα or both) and then compare the dually armed and single transgene armed viruses to identify an optimal vector for future IND guided studies.

摘要 该项目的首要目标是鉴定一种新的铅溶瘤病毒，用于成人的治疗。 胶质母细胞瘤(GBM)。溶瘤病毒(OV)治疗是一种很有前途的生物治疗方法，它优先靶向 用于溶解破坏的肿瘤细胞[1，2]。编码GM-CSF的溶瘤HSV-1(OHSV)衍生病毒 (IMLYGIC®)最近已被批准用于不可切除的转移性黑色素瘤[3，4]。在我们过去的努力中， 我们创造并测试了携带治疗性转基因的OHSV的治疗效果。这些病毒 已经在rHSVQ1(HSVQ)中创建：一种HSV病毒骨架，它对病毒神经的两个拷贝都被删除- 毒力基因ICP34.5，它包含一个干扰病毒ICP6插入的基因。这个主干具有衰减性 与G207完全相同的一种病毒，已被测试并发现在颅内术后的GBM患者中是安全的 在肿瘤内接种或在切除后肿瘤腔内接种时[5，7-10]。在这里，我们将创作一部小说 双臂溶瘤病毒(编码治疗性转基因：Vstat120和/或PTENα)，然后 比较双臂和单基因携带病毒以确定未来IND导向的最佳载体 学习。