Optimizing oncolytic virus therapy for glioblastoma

摘要 该项目的总体目标是确定一种新的主要溶瘤病毒，用于治疗成人肿瘤。 胶质母细胞瘤（GBM）。溶瘤病毒（OV）疗法是一种有前途的生物疗法，其优先靶向 肿瘤细胞进行裂解破坏[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素瘤[3，4]。在我们过去的努力中， 我们已经创造并测试了装备有治疗性转基因的oHSV的治疗功效。这些病毒 已在rHSVQ 1（HSVQ）中创建：一种HSV病毒骨架，缺失病毒神经元的两个拷贝， 毒力基因ICP34.5，并且它含有破坏病毒ICP 6中插入的基因。这个主干有衰减 与G207相同，G207是一种已经过测试并发现在颅内给药后对GBM患者安全的病毒。 接种到肿瘤中或给予切除后肿瘤腔[5，7-10]。在这里我们将创造一个小说 双臂溶瘤病毒（编码治疗性转基因：Vstat 120、PTENα或两者），然后 比较双武装和单转基因武装病毒，以确定未来IND指导的最佳载体 问题研究

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.