Abstract：
In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive \"conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)\" (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active \"cytomegalovirus enhancer and β-actin promoter\", provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active \"Rous sarcoma virus long terminal repeat\", not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials.
摘要：
总的来说,确保安全是新模式的重中之重。尽管携带免疫刺激转基因（OVI）的溶瘤病毒显示出一些希望，同时实现最大效力和最小化副作用的战略概念尚未得到充分探索。我们产生了多种survivin反应性的“有条件复制的腺病毒，可以靶向和治疗多种因子的癌细胞（m-CRAs）”（Surv。m-CRA）使用我们的m-CRA平台技术在各种启动子的下游配备粒细胞-巨噬细胞集落刺激因子（GM-CSF）转基因。我们仔细分析了它们在体内同基因叙利亚仓鼠癌模型中的治疗和不良反应。令人惊讶的是,常规OVI的瘤内注射，在组成型和强烈活性的“巨细胞病毒增强子和β-肌动蛋白启动子”下表达GM-CSF基因，引起全身和致死性GM-CSF循环，并缩短总生存期（OS）。相比之下,一种新的概念类型的OVI，在癌症占优势和轻度活性的E2F启动子或中度活性的“劳斯肉瘤病毒长末端重复序列”下表达GM-CSF，不仅消除了致命的不良事件，而且延长了OS和全身抗癌免疫力。我们的研究揭示了一个新概念，即由合适的上游启动子调节的免疫刺激转基因的最佳表达水平对于在OVI治疗中同时实现高安全性和最大治疗效果至关重要。这些结果为成功开发下一代OVI铺平了道路，并提醒研究人员正在进行的临床试验可能存在的问题。
