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名妇女被确诊(全球有240,000人)。死亡率为65%，大多数患者在5年内死亡。OC通常在晚期被诊断出来，因此很难治疗。虽然对化疗的初始反应很高，但大多数患者(80%)很快就会获得(铂)耐药性并复发。二线化疗/靶向生物药物在减缓进展方面只提供微乎其微的好处。新兴的免疫疗法增强了患者的免疫系统与癌症作斗争的能力，并作为有效的二线治疗提供了希望。然而，大多数(85%)OC肿瘤缺乏必要的免疫细胞/过程，使它们对免疫疗法没有反应。溶瘤病毒(OV)的作用是选择性地感染/摧毁癌细胞，同时刺激强烈的免疫反应(重新招募免疫细胞/解除与癌症相关的免疫抑制)。OVS的一个关键优势是能够用一个或多个可能在肿瘤内直接表达的协同治疗性转基因来武装它们(增强疗效/绕过毒性)。然而，现有的OV是从重新利用/普通实验室/野生型病毒衍生而来的，这些病毒既不是为了溶瘤而进化出来的，也不是为了全身递送而进化出来的，而是使用实验室细胞系或不能反映患者肿瘤的小鼠来开发/验证的。典型的武装策略选择1-2个转基因(从数千个选项中)，在基本模型上使用最佳猜测方法(通常取消选择在真实肿瘤中有效的候选基因，并且与病毒的协同作用很差)。他们几乎没有注意到优化转基因在病毒中的位置(有效表达转基因的关键变量)。他们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.