A novel platform for arming of candidate oncolytic viruses targeting immunologically cold metastatic ovarian cancer

卵巢癌（OC）是癌症死亡的第六大常见原因。每年有7，443名妇女被诊断出来（全球240，000人）。死亡率> 65%，大多数患者在5年内死亡，OC常在晚期被诊断，治疗困难，虽然化疗的初始反应很高，但大多数患者（>80%）很快获得（铂）耐药并复发。二线化疗/靶向生物制剂在减缓进展方面仅提供边际效益。新兴的免疫疗法使患者的免疫系统能够对抗癌症，并作为有效的二线治疗提供希望。然而，大多数（>85%）OC肿瘤缺乏必需的免疫细胞/过程，使得它们对免疫疗法无反应。溶瘤病毒（OV）通过选择性感染/破坏癌细胞而起作用，同时刺激强烈的免疫反应（募集免疫细胞/解除癌症相关的免疫抑制）。OV的一个关键优势是能够用一种/多种协同治疗转基因武装它们，所述协同治疗转基因可以直接在肿瘤内表达（增强功效/绕过毒性）然而，现有的OV来源于重新目的化的/常见的实验室/野生型病毒，其不是为了溶瘤用途或全身递送而进化的，而是使用反映患者肿瘤不佳的实验室细胞系或小鼠开发/验证的。典型的武装策略使用基本模型上的“最佳猜测”方法选择1-2个转基因（从数千个选项中）（通常取消选择在真实的肿瘤中具有功效并且与病毒协同作用差的候选物）。他们很少关注优化病毒内的转基因位置（有效转基因表达的关键变量）。理论家试图通过应用他们的破坏性OV平台来克服这些挑战。

Ovarian cancer (OC) is the 6th most common cause of cancer death. Annually \>7,443 women are diagnosed (\>240,000 globally). Mortality rates are \>65%, with most patients succumbing within 5-years.OC is frequently diagnosed at a late stage making it difficult to treat. Whilst initial response to chemotherapy is high, most patients (\>80%) quickly acquire (platinum-)resistance and relapse. Second-line chemotherapies/targeted-biologicals offer only marginal benefit in slowing progression.Emerging immunotherapies empower the patient's immune system to fight cancer and offer hope as effective second-line treatments. However, most (\>85%) OC tumours are devoid of essential immune cells/processes, making them unresponsive to immunotherapies.Oncolytic viruses (OVs) act by selectively infecting/destroying cancer cells, whilst simultaneously stimulating strong immune responses (recruiting immune cells/lifting cancer-associated immune suppression). A key strength of OVs is the ability to arm them with one/more synergistic therapeutic transgenes that may be expressed directly within the tumour (enhancing efficacy/bypassing toxicities).However, existing OVs are derived from re-purposed/common laboratory/wild-type viruses that are not evolved for oncolytic use nor systemic delivery, but instead developed/validated using laboratory cell-lines or mice that poorly reflect patient tumours. Typical arming strategies select 1-2 transgenes (from thousands of options) using a 'best-guess' approach on basic models (often de-selecting candidates with efficacy in real tumours, and poorly synergising with the virus). They give little attention to optimising transgene position within the virus (a critical variable for effective transgene expression).Theolytics seek to overcome these challenges through application of their disruptive OV Platform.