Effective Treatment of an Orthotopic Xenograft Model of Human Glioblastoma Using an EGFR-retargeted Oncolytic Herpes Simplex Virus
Effective Treatment of an Orthotopic Xenograft Model of Human Glioblastoma Using an EGFR-retargeted Oncolytic Herpes Simplex Virus
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DOI：
10.1038/mt.2012.211
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发表时间：
2013-03-01
影响因子：
12.4
通讯作者：
Glorioso, Joseph C.
中科院分区：
文献类型：
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作者：
Uchida, Hiroaki;Marzulli, Marco;Glorioso, Joseph C.
多形性胶质母细胞瘤（GBM）仍然是一种无法治愈的人脑恶性肿瘤。尽管使用溶瘤单纯疱疹病毒（oHSV）载体进行了有希望的临床前研究，但由于病毒在肿瘤细胞中复制效率低下，因此在患者中的疗效受到限制。这种令人失望的结果可以部分归因于这些病毒中的减毒突变，以防止在正常细胞中复制。或者，完全复制能力的HSV重新靶向肿瘤相关受体具有实现肿瘤特异性而不损害溶瘤活性的潜力。在这里，我们报告的HSV重靶向系统的建立，依赖于两个工程病毒糖蛋白，gD和gB的组合，介导高效的HSV感染完全通过识别胶质母细胞瘤细胞上大量表达的表皮生长因子受体（EGFR）。我们在体外和小鼠异位肿瘤模型中证明了疗效。证据表明，全身给药的病毒归巢的肿瘤质量。原位原代人GBM异种移植物的治疗显示出延长的存活率，高达73%的动物显示出完全反应，如通过磁共振成像所证实的。我们的研究描述了一种在胶质瘤模型中有效的HSV重靶向方法，并可能适用于治疗广泛的肿瘤类型。
Glioblastoma multiforme (GBM) remains an untreatable human brain malignancy. Despite promising preclinical studies using oncolytic herpes simplex virus (oHSV) vectors, efficacy in patients has been limited by inefficient virus replication in tumor cells. This disappointing outcome can be attributed in part to attenuating mutations engineered into these viruses to prevent replication in normal cells. Alternatively, retargeting of fully replication-competent HSV to tumor-associated receptors has the potential to achieve tumor specificity without impairment of oncolytic activity. Here, we report the establishment of an HSV retargeting system that relies on the combination of two engineered viral glycoproteins, gD and gB, to mediate highly efficient HSV infection exclusively through recognition of the abundantly expressed epidermal growth factor receptor (EGFR) on glioblastoma cells. We demonstrate efficacy in vitro and in a heterotopic tumor model in mice. Evidence for systemically administered virus homing to the tumor mass is presented. Treatment of orthotopic primary human GBM xenografts demonstrated prolonged survival with up to 73% of animals showing a complete response as confirmed by magnetic resonance imaging. Our study describes an approach to HSV retargeting that is effective in a glioma model and may be applicable to the treatment of a broad range of tumor types.