The use of mutant strains of oncolytic herpes simplex virus (oHSV) in early-phase human clinical trials for the treatment of glioblastoma multiforme (GBM) has proven safe, but limited efficacy suggests that more potent vector designs are required for effective GBM therapy. Inadequate vector performance may derive from poor intratumoral vector replication and limited spread to uninfected cells. Vector replication may be impaired by mutagenesis strategies to achieve vector safety, and intratumoral virus spread may be hampered by vector entrapment in the tumor-specific extracellular matrix (ECM) that in GBM is composed primarily of type IV collagen. In this report, we armed our previously described epidermal growth factor receptor (EGFR)vIII-targeted, neuronal microRNA-sensitive oHSV with a matrix metalloproteinase (MMP9) to improve intratumoral vector distribution. We show that vector-expressed MMP9 enhanced therapeutic efficacy and long-term animal survival in a GBM xenograft model.

在早期人体临床试验中使用溶瘤单纯疱疹病毒 (oHSV) 突变株治疗多形性胶质母细胞瘤 (GBM) 已被证明是安全的，但疗效有限表明需要更有效的载体设计才能有效治疗 GBM。载体性能不足可能源于肿瘤内载体复制不良和向未感染细胞的有限传播。为实现载体安全而采取的诱变策略可能会损害载体复制，而肿瘤特异性细胞外基质 (ECM) 中的载体截留可能会阻碍肿瘤内病毒的传播，而在 GBM 中，ECM 主要由 IV 型胶原组成。在本报告中，我们用基质金属蛋白酶 (MMP9) 武装了之前描述的表皮生长因子受体 (EGFR)vIII 靶向、神经元 microRNA 敏感的 oHSV，以改善瘤内载体分布。我们表明，载体表达的 MMP9 增强了 GBM 异种移植模型中的治疗效果和长期动物存活率。