基于三维结构指导重组塞内加谷病毒在基因治疗方向的优化

Oncolytic virus is an important branch of tumor immunotherapy。 In recent years, Seneca Vally Virus has been demonstrated its anticancer ability in phase I clinical trials of pediatric solid tumors and phase II clinical trials of small cell lung cancer. But now there are still problems: after the human infection with Seneca Vally Virus, it will establish immunity against the virus within three weeks and then eliminate the virus; viral oncolytic efficiency needs to be improved. This project is based on the above-mentioned problems for in-depth research, by analyzing the three-dimensional structure of Seneca Vally Virus and its neutralizing antibody complex, from the perspective of structural biology to explain the interaction between virus and antibody, to provide the structural biological basis for virus modification, try to change the non-essential part to escape the role of the immune system; and through the three-dimensional structure analysis of the virus and its receptor, optimize the amino acid residues on the surface of the virus, increase the ability of the virus to bind to the receptor, improve the virus Infection efficiency and oncolytic effect. In the end, it is hoped that the recombinant virus can escape the immune system, effectively invade and kill cancer cells. For the recombinant Seneca Vally Virus can provide important ideas, methods and guidance for the oncolytic virus in clinical treatment work in China.

溶瘤病毒是肿瘤免疫疗法的重要分支。近几年内，塞内加谷病毒已经在小儿实体瘤 I 期临床试验和小细胞肺癌 II 期临床试验中证明了其抗癌能力。但依然有些问题值得研究与解决，例如：人体感染塞内加谷病毒后会在三周内建立对病毒的免疫体系，治疗效果与机体快速免疫识别有关；病毒溶瘤效率有待提高。本项目正是基于上述问题进行深入研究，通过解析塞内加谷病毒与其中和抗体复合物的三维结构，从结构生物学的角度阐释病毒与抗体之间的相互作用方式，为改造病毒提供结构生物学基础，尝试改变病毒非必需部分，从结构生物学的角度优化重组病毒使其逃避免疫系统的作用；并且通过对病毒与其受体的三维结构分析，对病毒表面的氨基酸残基进行优化，增加病毒与受体的结合能力，提高病毒的感染效率与溶瘤效果。最终希望重组病毒可以逃避免疫系统，高效的入侵并杀死癌细胞。为重组塞内加谷病毒作为溶瘤病毒，在我国临床治疗中得到应用提供重要的科研基础。

大量研究表明，塞内加谷病毒(SVV)在靶向小细胞肺癌(SCLC)中显示出足够的溶瘤效果。然而，使用溶瘤病毒治疗非小细胞肺癌(NSCLC，占肺癌病例的85%)由于中和抗体的过滤和生殖能力有限，一直受到抵制。在这里，我们利用结构生物学和逆向遗传学优化了新的溶瘤SVV突变体(病毒受体相关突变体SVV- s177a和病毒抗原肽相关变异SVV- p60s) ，增强了传染性，降低了免疫原性。nsclc小鼠模型的结果表明，野生型SVV-HB将PBS组的中位总生存期(mOS)从11天延长到19天。值得注意的是，新发现的突变显著(p < 0.001)将mOS从对照组的11天延长到SVV-S177A队列和SVV-P60S队列的23天。综上所述，我们提出了一种结构引导的基因修饰策略来优化溶瘤SVV，并为开发针对非敏感NSCLC的溶瘤病毒治疗提供了一个候选方案。