Engineering Newcastle Disease Virus as an Oncolytic Vector for Intratumoral Delivery of Immune Checkpoint Inhibitors and Immunocytokines
Engineering Newcastle Disease Virus as an Oncolytic Vector for Intratumoral Delivery of Immune Checkpoint Inhibitors and Immunocytokines
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DOI：
10.1128/jvi.01677-19
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发表时间：
2020-02-01
影响因子：
5.4
通讯作者：
Palese, Peter
中科院分区：
文献类型：
--
作者：
Vijayakumar, Gayathri;McCroskery, Stephen;Palese, Peter
新城疫病毒(NDV)具有在肿瘤细胞中复制的能力，并有可能克服肿瘤微环境固有的免疫抑制特性，因此是一种有吸引力的肿瘤溶解免疫治疗候选病毒。在过去的几年里，检查点阻断免疫疗法的出现代表了癌症治疗的范式转变。然而，在临床研究中，尤其是在联合治疗组中，CTLA4和PD1通路阻断导致的严重免疫相关不良事件的发生率令人担忧。使用细胞因子的免疫疗法也得到了广泛的探索，但在临床试验中，它们与不良事件有关。设计表达检查点阻断抗体和细胞因子的溶瘤载体可以通过将免疫调节有效载荷集中在疾病部位，为降低与全身治疗相关的临床毒性提供一条途径。在这项研究中，我们设计了六种不同的重组病毒：表达检查点抑制物(rNDV-anti-PD1和rNDV-anti-PDL1)的NDV；超级激动剂(rNDV-anti-CD28)；以及免疫细胞因子，其中抗体与免疫刺激细胞因子融合，如IL-12(rNDV-anti-CD28-小鼠IL-12[mIL-12]、rNDV-anti-PD1-mIL-12和rNDV-anti-PDL1-mIL-12)。在高度侵袭性的单侧和双侧B16-F10小鼠黑色素瘤模型中，这六种工程病毒诱导的肿瘤控制和存活都有好处，这表明了一种非内窥镜效应。这些数据有力地证明了可以进行进一步临床评估的概念。重要的检查点抑制剂疗法显示出巨大的疗效，但也经常出现严重的副作用--特别是当同时使用这类药物时。同样，许多在动物模型中显示出希望的研究免疫治疗药物，由于系统给药时的剂量限制毒性，在临床试验中失败了。这项研究利用小鼠黑色素瘤模型来评估瘤内注射重组NDV的疗效，重组NDV被设计成表达多种免疫治疗蛋白，并在人类中产生了良好的副作用。我们的结果表明，这些重组新城疫病毒的瘤内给药，特别是当与全身CTLA4检查点抑制相结合时，在治疗和未治疗的肿瘤中发挥了强大的作用，表明了全身抗肿瘤反应。瘤内注射表达免疫治疗蛋白的rNDV可能是一种针对与抗肿瘤免疫最相关的免疫细胞群的有效方法，并允许我们限制全身免疫治疗药物的使用。
Newcastle disease virus (NDV) is an attractive candidate for oncolytic immunotherapy due to its ability to replicate in tumor cells and potentially to overcome the inherently immunosuppressive nature of the tumor microenvironment. The advent of checkpoint blockade immunotherapy over the past few years represents a paradigm shift in cancer therapy. However, the prevalence of severe immune-related adverse events with CTLA4 and PD1 pathway blockade in clinical studies, especially in combination therapy groups, is a cause for concern. Immunotherapies with cytokines have also been extensively explored, but they have been associated with adverse events in clinical trials. Oncolytic vectors engineered to express checkpoint blockade antibodies and cytokines could provide an avenue for reducing the clinical toxicity associated with systemic therapy by concentrating the immunomodulatory payload at the site of disease. In this study, we engineered six different recombinant viruses: NDVs expressing checkpoint inhibitors (rNDV-anti-PD1 and rNDV-anti-PDL1); superagonists (rNDV-anti-CD28); and immunocytokines, where the antibodies are fused to an immunostimulatory cytokine, such as interleukin 12 (IL-12) (rNDV-anti-CD28-murine IL-12 [mIL-12], rNDV-anti-PD1-mIL-12, and rNDV-anti-PDL1-mIL-12). These six engineered viruses induced tumor control and survival benefits in both highly aggressive unilateral and bilateral B16-F10 murine melanoma models, indicative of an abscopal effect. The data represent a strong proof of concept on which further clinical evaluation could build.IMPORTANCE Checkpoint inhibitor therapy has shown tremendous efficacy, but also frequent and often severe side effects- especially when multiple drugs of the class are used simultaneously. Similarly, many investigational immunotherapy agents, which have shown promise in animal models, have failed in clinical trials due to dose-limiting toxicity when administered systemically. This study utilized a murine melanoma model to evaluate the efficacy of intratumoral injections of recombinant NDVs engineered to express multiple immunotherapeutic proteins with well-documented side effects in humans. Our results indicate that intratumoral administration of these recombinant NDVs, particularly when combined with systemic CTLA4 checkpoint inhibition, exerts a robust effect in treated and nontreated tumors, indicative of a systemic antitumoral response. The intratumoral delivery of rNDVs expressing immuno-therapeutic proteins may be an effective method of targeting the immune cell populations most relevant for antitumoral immunity and allowing us to restrict the use of systemic immunotherapy agents.