Oncorus, Inc., Cambridge, MA, USA.
Nat Commun. 2022 Oct 7;13(1):5907. doi: 10.1038/s41467-022-33599-w.
The therapeutic effectiveness of oncolytic viruses (OVs) delivered intravenously is limited by the development of neutralizing antibody responses against the virus. To circumvent this limitation and to enable repeated systemic administration of OVs, here we develop Synthetic RNA viruses consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21, we demonstrate vRNA delivery and replication, virus assembly, spread and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. Synthetic-SVV replication in tumors promotes immune cell infiltration, remodeling of the tumor microenvironment, and enhances the activity of anti-PD-1 checkpoint inhibitor. In mouse and non-human primates, Synthetic-SVV is well tolerated reaching exposure well above the requirement for anti-tumor activity. Altogether, the Synthetic RNA virus platform provides an approach that enables repeat intravenous administration of viral immunotherapy.
静脉内递送溶瘤病毒（OVs）的治疗效果受到针对病毒的中和抗体反应的发展的限制。为了规避这一限制并实现 OV 的重复系统给药，我们在这里开发了由病毒 RNA 基因组（vRNA）在脂质纳米颗粒中形成的合成 RNA 病毒。对于两种合成 RNA 病毒候选药物，即塞内卡谷病毒（SVV）和柯萨奇病毒 A21，我们证明了 vRNA 的递送和复制、病毒组装、肿瘤细胞的扩散和裂解，导致强大的抗肿瘤功效，即使在血液中存在 OV 中和抗体的情况下也是如此。肿瘤中的合成-SVV 复制促进免疫细胞浸润、肿瘤微环境重塑，并增强抗 PD-1 检查点抑制剂的活性。在小鼠和非人类灵长类动物中，合成-SVV 的耐受性良好，达到了抗肿瘤活性所需的暴露量以上。总之，合成 RNA 病毒平台提供了一种能够实现病毒免疫疗法重复静脉内给药的方法。
