Development of an effective therapeutic regime for preventing cancer recurrence after surgery using a novel viro-immunotherapeutic agent

尽管手术技术取得了进步，但口腔鳞状细胞癌（最常见的口腔癌形式，2012年全球有39.8万例患者）的生存率在过去20年没有改善。50-70%的患者因局部复发和远处转移而在5年内死亡。复发或转移性头颈部鳞状细胞癌患者的预后通常较差。大多数系列的中位生存期为6至9个月，取决于患者和疾病相关因素。因此，迫切需要新的方法来防止术后复发和转移。术后复发和转移的主要来源是微小残留病（MRD），其在手术切除后在清除边缘以外的显微沉积物和微转移中仍然存在。越来越多的证据表明，手术干预实际上可以通过多种机制促进肿瘤复发和远处转移，包括抑制宿主免疫细胞，如自然杀伤细胞（NK）细胞和T细胞。肿瘤靶向溶瘤病毒（tov）是一种有吸引力的癌症治疗方法，因为它们通过复制和传播输入剂量的病毒在目标肿瘤中选择性扩增，最重要的是通过多种机制杀死肿瘤，特别是它们可以诱导针对MRD的全身抗肿瘤免疫。我们最近创造了一种新的肿瘤靶向溶瘤痘苗病毒。用这种病毒治疗导致NK细胞的强烈激活和强大的肿瘤特异性免疫，并在手术前在几种癌症模型中静脉注射这种病毒，显著减少手术后的肺转移。为了进一步提高其抗肿瘤功效，我们现在已经设计了带有特定治疗基因的突变病毒，可以进一步提高NK细胞和抗肿瘤T细胞的活性。在本项目中，我们将在一系列模拟癌症患者临床情况的肿瘤模型中评估这种新型免疫治疗剂预防癌症术后复发和转移的可行性、有效性和安全性。到本项目结束时，将开发出最佳的治疗方案。这些数据将为将该疗法转化为临床试验提供概念证明。这种新方法可能在未来显著提高头颈癌患者的生存率。

Despite advances in surgical techniques, survival rates for oral sqamous cell carcinoma, the most common form of oral cancer (398,000 patients worldwide in 2012), have not improved for the last 20 years. 50-70% of patients die within 5 years due to local recurrence and remote metastasis. The prognosis of patients with recurrent or metastatic head and neck squamous cell cancer is generally poor. The median survival in most series is six to nine months depending upon patient- and disease-related factors. Therefore, new approaches are urgently needed to prevent recurrence and metastasis after surgery. The main source for recurrence and metastasis after surgery is minimal residual disease (MRD) that remains in situ after surgical resection in microscopic deposits beyond the clearance margins and in micrometastases. There is increasing evidence that surgical intervention can actually promote tumour recurrence and distant metastases by several mechanisms including suppression of host immune cells, such as natural killer (NK) cells and T cells. Tumour-targeted oncolytic viruses (TOVs) are attractive therapeutics for cancer because they selectively amplify through replication and spread the input dose of virus in the target tumour and most importantly kill tumours by multiple mechanisms, in particular they can induce systemic anti-tumour immunity that can target MRD. We have recently created a novel tumour-targeted oncolytic vaccinia virus. Treatment with this virus resulted in a strong NK cell activation and potent tumour-specific immunity, and dramatically reduced lung metastasis after surgery in several cancer models when the virus was intratumurally injected before surgery. To improve its anti-tumour efficacy further, we now have engineered the mutant virus with a particular therapeutic gene that can boost the activity of NK cells and anti-tumour T cells further. In this project, we will evaluate the feasibility, efficacy and safety of this novel immunotherapeutic agent for preventing recurrence and metastasis of cancer after surgery in a serious of tumour models that can mimic the clinical situation of cancer patients. By the end of this project, an optimal therapeutic regime will be developed. These data will provide proof of concept for translation of the regime into clinical trials. This new approach may significantly improve the survival of head and neck cancer patients in the future.