Abstract：
Immunotherapy is a powerful tool for cancer treatment, but the pleiotropic nature of cytokines and immunological agents strongly limits clinical translation and safety. To address this unmet need, we designed and characterised a systemically targeted cytokine gene delivery system through transmorphic encapsidation of human recombinant adeno-associated virus DNA using coat proteins from a tumour-targeted bacteriophage (phage). We show that Transmorphic Phage/AAV (TPA) particles provide superior delivery of transgenes over current phage-derived vectors through greater diffusion across the extracellular space and improved intracellular trafficking. We used TPA to target the delivery of cytokine-encoding transgenes for interleukin-12 (IL12), and novel isoforms of IL15 and tumour necrosis factor alpha (TNF α ) for tumour immunotherapy. Our results demonstrate selective and efficient gene delivery and immunotherapy against solid tumours in vivo, without harming healthy organs. Our transmorphic particle system provides a promising modality for safe and effective gene delivery, and cancer immunotherapies through cross-species complementation of two commonly used viruses.
摘要：
免疫疗法是癌症治疗的有力工具,但是细胞因子和免疫试剂的多效性强烈限制了临床翻译和安全性。为了解决这个未满足的需求，我们使用肿瘤靶向噬菌体（噬菌体）的外壳蛋白，通过人重组腺相关病毒DNA的转型衣壳化，设计并表征了系统靶向的细胞因子基因递送系统。我们表明，通过跨细胞外空间的更大扩散和改善的细胞内运输，跨噬菌体/AAV（TPA）颗粒提供了比当前噬菌体衍生载体更好的转基因递送。我们使用TPA靶向递送白细胞介素-12（IL12）的细胞因子编码转基因，以及用于肿瘤免疫治疗的IL15和肿瘤坏死因子α（TNFα）的新型同工型。我们的结果证明了体内针对实体瘤的选择性和有效的基因递送和免疫疗法，不伤害健康的器官。我们的变性粒子系统为安全有效的基因传递提供了一种有希望的方式，以及通过两种常用病毒的跨物种互补进行癌症免疫疗法。
