Experimental Viral Therapy for the Treatment of Malignant Glioma Using Recombinant Herpes Simplex Virus Type 1

我们正在探索一种利用基因工程减毒复制能力强的1型单纯疱疹病毒（HSV-1）治疗恶性脑肿瘤的新方法。我们之前的研究表明，胸苷激酶缺陷的HSV-1突变体（dlsptk）可以破坏人类胶质瘤细胞，允许在分裂的肿瘤细胞中复制，但不允许在非分裂细胞中复制。我们假设这种HSV-1突变体可能在活跃生长的肿瘤细胞中复制，并有效地杀死恶性脑肿瘤，同时保留正常脑细胞。为了使这种疗法成为一种有效的临床选择，我们创造了一种单纯疱疹病毒1型多重缺失突变体，它对治疗人类恶性脑肿瘤具有良好的性能。这个突变体被命名为G207，在gamma34.5位点和lacZ基因插入处都有1.0 kb的缺失，使ICP6位点失活。G207引起扩散感染，杀死单层培养的人类胶质瘤细胞。在患有皮下或脑内U-87MG胶质瘤的裸鼠中，瘤内接种G207可降低肿瘤生长和/或延长生存时间。G207对小鼠和对HSV敏感的非人灵长类动物脑内接种无毒性。这些结果激发了人们对其可能用于治疗恶性脑肿瘤的临床试验的兴趣。

We are exploring a novel experimental treatment for malignant brain tumors utilizing a genetically engineered attenuated replication-competent herpes simplex virus type 1 (HSV-1). Our previos studies demonstrated that a thymidine kinase-deficient HSV-1 mutant(dlsptk), could destroy human glioma cells, allowing for replication in dividing tumor cells but not in non-dividing cells. We hypothesized that such HSV-1 mutants might replicate in actively growing tumor cells and effectively kill malignant brain tumors while sparing normal brain cells. In order for this therapy to become an effective clinical choice, we have created a multiple deletion mutant of herpes simple virus type 1 which has favorable properties for the treatment of human malignant brain tumors. This mutant, termed G207, has 1.0 kb deletions at both gamma34.5 loci and a lacZ gene insertion inactivating the ICP6 locus. G207 causes a spreading infection killing human glioma cells in monolayr cultures. In nude mice harboring subcutaneous or intracerebral U-87MG gliomas, intraneoplastic inoculation of G207 causes decreased tumor growth and/or prolonged survival. G207 is avirulent upon intracerebral inoculation of mice and HSV sensitive non-human primates. These results have stimulated interest in its possible clinical trial for the treatment of malignant brain tumors.