抗PD-1抗体SCFV基因重组水泡口炎病毒（VSV-Anti-PD-1）抗肿瘤作用及免疫机制研究

免疫共刺激分子PD-1作为负性调节分子，在肿瘤微环境的免疫细胞中高表达，能形成抑制性免疫微环境，在肿瘤免疫逃逸中起关键作用。已证实抗PD-1能够打破免疫耐受，给患者带来获益，但全身给药诱发的免疫相关性疾病以及高额的费用限制了其应用。故肿瘤微环境局部抗PD-1治疗有望更好激活免疫，且减少全身给药毒性并降低花费，采用溶瘤病毒局部表达抗PD-1抗体SCFV活性片段是一个有效方法。我们前期证实水泡口炎病毒（VSV）能有效促进肿瘤细胞凋亡和影响肿瘤免疫微环境，且成功导入生长因子等基因，是一种理想的基因导入载体。本课题拟通过瘤内导入抗PD-1抗体SCFV活性片段和VSV的重组病毒（VSV-Anti-PD-1），达到局部高表达抗PD-1活性片段来抑制PD-1信号、激活抗肿瘤免疫。本项目将探索VSV-Anti-PD-1重组病毒的靶向投递效果及抗肿瘤作用机制，为抗PD-1免疫治疗提供全新的安全、有效的治疗策略。

Immune costimulatory molecule PD-1， as a negative regulator of immune，plays a key role in mediating tumor immune escape with high expression in immune cells in the tumor microenvironment resulting in an inhibitory immune microenvironment. Clinical studies have demonstrated that targeting PD-1 signal can break immune tolerance and bring clinical benefit in cancer treatment. However, systemic administration inducing immune disease and expensive costs limit its application. Therefore, local anti- PD-1 treatment is expected to be better immune therapy with less toxicity and cost compared of systemic administration. Using oncolytic viruses to local express active anti-PD-1 SCFV fragment is a valid choice. We previously have demonstrated vesicular stomatitis virus (VSV) therapy can effectively promote tumor cell apoptosis and affect tumor immune microenvironment. With successful importing epidermal growth factor, VSV is the ideal therapy vectors. Intratumoral injection of VSV-Anti-PD-1 recombinant virus can express the Anti-PD-1 active fragments and regulate the immune microenvironment by inhibiting PD-1 signal and activating the anti- tumor immunity. Implementation of this project is expected to verify the anti-tumor efficacy of VSV-Anti-PD-1 recombinant virus and analyze related immune mechanisms, which provides a new security, effective treatment strategies for tumor immunotherapy of Anti-PD-1.