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Abstract：
Numerous studies have illustrated that the Seneca Valley virus (SVV) shows sufficient oncolytic efficacy targeting small cell lung cancer (SCLC). However, the therapeutics of nonsmall cell lung carcinoma (NSCLC, accounts for 85% of lung cancer cases) using oncolytic virus have been resisting due to the filtration of neutralizing antibody and limited reproduction capacity. Here, we employed structural biology and reverse genetics to optimize novel oncolytic SVV mutants (viral receptor-associated mutant SVV-S177A and viral antigenic peptide-related variant SVV-S177A/P60S) with increased infectivity and lower immunogenicity. The results of the NSCLC-bearing athymic mouse model demonstrated that wild-type (wt) SVV-HB extended the median overall survival (mOS) from 11 days in the PBS group to 19 days. Notably, the newly discovered mutations significantly (P < 0.001) prolonged the mOS from 11 days in the control cohort to 23 days in the SVV-S177A cohort and the SVV-S177A/P60S cohort. Taken together, we present a structure-guided genetic modification strategy for oncolytic SVV optimization and provide a candidate for developing oncolytic viral therapy against nonsensitive NSCLC. IMPORTANCE Nonsmall cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases (more than 1.85 million cases with 1.48 million deaths in 2020). In the present study, two novel oncolytic SVV mutants modified based on structural biology and reverse genetics (viral receptor-associated mutant SVV-S177A and viral antigenic peptide-related mutant SVV-S177A/P60S) with increased infectivity or lower immunogenicity significantly (P < 0.001) prolonged the mOS from 11 days in the control cohort to 23 days in the SVV-S177A cohort and the SVV-S177A/P60S cohort in the NSCLC-bearing athymic mouse model, which may provide the direction for modifying SVV to improve the effect of oncolysis.
摘要：
许多研究表明，SenecaValley病毒（SVV）显示出足够的靶向小细胞肺癌（SCLC）的溶瘤功效。然而,非小细胞肺癌(NSCLC，占肺癌病例的85％）由于中和抗体的过滤和有限的繁殖能力，使用溶瘤病毒一直具有抵抗力。这里,我们利用结构生物学和反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体SVV-S177A/P60S),其感染性增加,免疫原性降低.携带NSCLC的无胸腺小鼠模型的结果表明,野生型(wt)SVV-HB将PBS组中的中位总生存期(mOS)从11天延长至19天。值得注意的是,在SVV-S177A队列和SVV-S177A/P60S队列中,新发现的突变显著(P<0.001)将mOS从对照组的11天延长至23天.一起来看,我们提出了一种用于溶瘤SVV优化的结构指导的遗传修饰策略,并为开发针对非敏感性NSCLC的溶瘤病毒治疗提供了候选方案.重要性非小细胞肺癌（NSCLC）约占肺癌病例的85％（2020年超过185万病例，148万死亡）。在本研究中,两个基于结构生物学和反向遗传学修饰的新型溶瘤SVV突变体（病毒受体相关突变体SVV-S177A和病毒抗原性肽相关突变体SVV-S177A/P60S）具有增加的感染性或降低的免疫原性，显着（P<0.001）将mOS从对照组的11天延长到了SVV-S177A队列和携带SVV-S177A/P60S小鼠模型的23天这为改良SVV提高溶瘤效果提供了方向。
