Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA.
J Virol. 2018 Sep 12;92(19). doi: 10.1128/JVI.00879-18. Print 2018 Oct 1.
We are pursuing cancer immunotherapy with a neuro-attenuated recombinant poliovirus, PVSRIPO. PVSRIPO is the live attenuated type 1 (Sabin) poliovirus vaccine carrying a heterologous internal ribosomal entry site (IRES) of human rhinovirus type 2 (HRV2). Intratumoral infusion of PVSRIPO is showing promise in the therapy of recurrent WHO grade IV malignant glioma (glioblastoma), a notoriously treatment-refractory cancer with dismal prognosis. PVSRIPO exhibits profound cytotoxicity in infected neoplastic cells expressing the poliovirus receptor CD155. In addition, it elicits intriguing persistent translation and replication, giving rise to sustained type I interferon (IFN)-dominant proinflammatory stimulation of antigen-presenting cells. A key determinant of the inflammatory footprint generated by neoplastic cell infection and its role in shaping the adaptive response after PVSRIPO tumor infection is the virus's inherent relationship to the host's innate antiviral response. In this report, we define subversion of innate host immunity by PVSRIPO, enabling productive viral translation and cytopathogenicity with extremely low multiplicities of infection in the presence of an active innate antiviral IFN response. Engaging innate antiviral responses is considered key for instigating tumor-antigen-specific antitumor immunity with cancer immunotherapy approaches. However, they are a double-edged sword for attempts to enlist viruses in such approaches. In addition to their role in the transition from innate to adaptive immunity, innate antiviral IFN responses may intercept the viral life cycle in cancerous cells, prevent viral cytopathogenicity, and restrict viral spread. This has been shown to reduce overall antitumor efficacy of several proposed oncolytic virus prototypes, presumably by limiting direct cell killing and the ensuing inflammatory profile within the infected tumor. In this report, we outline how an unusual recalcitrance of polioviruses toward innate antiviral responses permits viral cytotoxicity and propagation in neoplastic cells, combined with engaging active innate antiviral IFN responses.
我们正在研究用神经减毒重组脊髓灰质炎病毒（PVSRIPO）进行癌症免疫治疗。PVSRIPO 是携带人鼻病毒 2 型（HRV2）异源内部核糖体进入位点（IRES）的活减毒 1 型（Sabin）脊髓灰质炎病毒疫苗。PVSRIPO 瘤内输注在复发性世界卫生组织 4 级恶性胶质瘤（胶质母细胞瘤）的治疗中显示出希望，这是一种预后不良的治疗难治性癌症。PVSRIPO 在表达脊髓灰质炎病毒受体 CD155 的感染性肿瘤细胞中表现出强烈的细胞毒性。此外，它还引发了有趣的持续翻译和复制，导致持续的 I 型干扰素（IFN）主导的促炎刺激抗原呈递细胞。肿瘤细胞感染产生的炎症足迹的关键决定因素及其在 PVSRIPO 肿瘤感染后塑造适应性反应中的作用是病毒与其宿主固有抗病毒反应的固有关系。在本报告中，我们定义了 PVSRIPO 对先天宿主免疫的颠覆，使病毒在具有活跃的先天抗病毒 IFN 反应的情况下，以极低的感染复数进行有效的病毒翻译和细胞病变作用。参与先天抗病毒反应被认为是通过癌症免疫治疗方法引发肿瘤抗原特异性抗肿瘤免疫的关键。然而，对于试图在这些方法中利用病毒来说，它们是一把双刃剑。除了在先天免疫向适应性免疫的转变中的作用外，先天抗病毒 IFN 反应可能会在癌细胞中拦截病毒生命周期，防止病毒细胞病变，并限制病毒传播。这已被证明会降低几种拟议的溶瘤病毒原型的整体抗肿瘤疗效，推测是通过限制感染肿瘤内的直接细胞杀伤和随之而来的炎症特征。在本报告中，我们概述了脊髓灰质炎病毒对先天抗病毒反应的异常抗性如何允许病毒在肿瘤细胞中产生细胞毒性和增殖，同时结合了活跃的先天抗病毒 IFN 反应。
