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）的生存率（2012年全球有398，000例患者）在过去20年中并未改善。50 - 70%的患者在5年内死于局部复发和远处转移。复发性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手术后的复发和转移。术后复发和转移的主要来源是微小残留病（MRD），其在手术切除后以超出清除边缘的显微镜沉积物和微转移灶的形式留在原位。越来越多的证据表明，手术干预实际上可以通过几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（NK）细胞和T细胞。肿瘤靶向溶瘤病毒（TOV）是有吸引力的癌症治疗药物，因为它们通过复制选择性扩增并在靶肿瘤中传播输入剂量的病毒，最重要的是通过多种机制杀死肿瘤，特别是它们可以诱导可以靶向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牛痘病毒。用这种病毒治疗导致强烈的NK细胞活化和有效的肿瘤特异性免疫，并且当在手术前瘤内注射病毒时，在几种癌症模型中手术后显著减少肺转移。为了进一步提高其抗肿瘤功效，我们现在已经用一种特殊的治疗基因改造了突变病毒，这种基因可以进一步增强NK细胞和抗肿瘤T细胞的活性。在这个项目中，我们将评估这种新型免疫抑制剂在一系列能够模拟癌症患者临床情况的肿瘤模型中用于预防癌症术后复发和转移的可行性、有效性和安全性。到该项目结束时，将制定最佳治疗方案。这些数据将为将该方案转化为临床试验提供概念证明。这种新方法可能会在未来显着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.