肺癌靶向治疗的疱疹溶瘤病毒开发研究

项目名称： 肺癌靶向治疗的疱疹溶瘤病毒开发研究

项目编号： No.81472826

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 周国瑛

作者单位： 广州医科大学

项目金额： 75万元

中文摘要： 减毒性疱疹溶瘤病毒(oHSV)在国外进入不同的实体瘤治疗临床试验，但在肺癌治疗中遇到障碍。原因是微量病毒进入肺细胞，可能激起免疫应激反应导致肺功能的丧失，针对肺癌治疗设计靶向性疱疹溶瘤病毒迫在眉睫。申请人是靶向性疱疹溶瘤病毒的发明人，研究获4项国际专利，成果被应用在恶性脑瘤，乳腺癌和卵巢癌的治疗中。本研究设计针对肺癌细胞表面蛋白，构建靶向性疱疹溶瘤病毒oHSV，达到靶向高效安全的治疗目的。靶向性方面，将三种不同类型的肺癌表面蛋白的单链抗体（ScFv）在病毒受体识别蛋白gD中定点表达，再敲除gD对正常细胞的识别，使病毒只识别肺癌细胞；高效性方面，以野生型病毒为模板，保持天然活力；安全性方面，在病毒中表达抑制细胞因子风暴的SOCS3；同时敲除病毒危险抗原 基因，弱化免疫应激反应。构建的重组病毒将在相应的肺癌细胞表面蛋白细胞系和动物模型中进行鉴定评估，为新药开发提供安全高效的保障。

中文关键词： C05_气管；支气管；肺肿瘤；疱疹溶瘤病毒；靶向；安全性；细胞因子风暴

英文摘要： Oncolytic virotherapy exploits the ability of viruses to infect and kill cancer cells. Numerous clinical trials demonstrated that oncolytic herpes simplex virus 1 (oHSV) is effective against a subpopulation of solid cancers, and can be administered repeatedly. Yet it is confronted with problems as to treatment of lung cancer for minor entry of viruses may cause cytokine storm to lung and functionally destroy it. Building on my long-term experience on the molecular mechanisms by which HSV-1 enters cells, I have devised a strategy to re-design HSVs, such that they exclusively infect lung cancer cells that carry on their surface a specific receptor of choice (retargeting). They no longer infect non-cancer cells. Once the retargeted HSVs enter the specific lung cancer cells, they counteract innate responses and destroy the cancer cells. The aims of this proposal are: AIM 1, replace the Ig-folded core in the receptor-binding virion glycoprotein gD with three anti-lung cancer surface protein single-chain antibodies. AIMs 2: design robust retargeted-HSVs based on wide-type virus to boost its anti-cancer capability. AIM 3: express SOCS3 to inhibit cytokine storm and delete danger antigens from HSV-1 viral proteins to avoid potentially fatal immune reaction. AIMs 4: develop cancer cell lines and animal models acceptable for evaluation of retargeted-HSVs.

英文关键词： lung cancer;oncolytic HSV;targeting;safety;cytokine storm