HERPES SIMPLEX VIRUS IN THE TREATMENT OF ORAL CANCER

我们将开发用于治疗口腔癌的1型单纯疱疹病毒（HSV- 1）的新菌株。 HSV- 1具有作为口腔癌的治疗工具的潜力，因为它感染作为其天然宿主组织的口腔上皮，具有高度细胞毒性，并且从一个细胞迅速扩散到另一个细胞。 HSV-1的唯一缺点是它可以传播到神经系统，导致瘫痪和死亡。 为了防止这种情况，我们将开发一种新的病毒株，其复制仅限于口腔癌细胞。 这将通过去除控制必需病毒基因表达的启动子，并用在口腔癌细胞中有活性但在神经系统细胞中无活性的启动子取代它来实现。 我们将通过添加细胞因子的基因来增加病毒的抗肿瘤效果。 这将增加对感染肿瘤的局部免疫反应。 然后，我们将利用更昔洛韦被HSV-1激活时发生的抗肿瘤旁观者效应，使抗肿瘤效果更强。 我们期望肿瘤限制性病毒、增强的局部免疫应答和抗肿瘤旁观者效应的三重组合在口腔癌实验模型的治疗中将比其他治疗更有效，并且可能在未来导致人体试验。

We will develop new strains of Herpes simplex virus type-1 (HSV- 1) for use in the treatment of oral cancer. HSV- 1 has potential as a therapeutic tool for oral cancer since it infects oral epithelium as its natural host tissue, is highly cytotoxic, and spreads rapidly from one cell to another. The only disadvantage of HSV-1 is that it can spread to the nervous system, causing paralysis and death. To prevent this, we will develop a new strain of the virus whose replication is limited to oral cancer cells. This will be done by removing a promoter that controls expression of an essential viral gene, and replacing it with a promoter that is active in oral cancer cells but not in nervous- system cells. We will increase the anti-tumor effect of the virus by adding a gene for a cytokine. This will increase the local immune response to the infected tumor. We will then make the anti-tumor effect even stronger by exploiting the anti-tumor bystander effect that occurs when ganciclovir is activated by HSV-1. We expect that the triple combination of a tumor- restricted virus, enhanced local immune response, and anti-tumor bystander effect will be more effective in treatment of an experimental model of oral cancer than other treatments, and could lead to human trials in the future.