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

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.

Local recurrence and remote metastasis are major challenges to overcome in order to improve the survival of cancer patients after surgery. The main source for these is the minimal residual disease (MRD) that remains in situ after resection in microscopic deposits beyond the clearance margins and in clinically undetectable micrometastases. There is increasing evidence that surgical intervention can actually promote tumour recurrence and distant metastases by several mechanisms including suppression of NK cells and marked Th2 polarisation. 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 of action - in particular they can induce systemic anti-tumour immunity that can target MRD. We have recently created a novel tumour-targeted oncolytic vaccinia virus (VVTKN1L). Treatment with this virus resulted in strong NK cell activation and potent tumour-specific immunity, and dramatically reduced lung metastasis after surgery in several cancer models when used as a neo-adjuvant therapeutic agent. To improve its anti-tumour efficacy further, we armed VVTKN1L with several immunomodulatory genes. Strikingly, treatment of subcutaneous pancreatic cancer tumours with VVTKN1L-IL12 resulted in complete eradication of tumours in 86% of mice and complete resistance to subsequent challenge with the same tumour type. 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 subcutaneous and orthotopic models of oral carcinoma in immunocompetent animals as well as a CD34+ humanised NSG mouse tumour model. An optimal therapeutic regime including route, doses and time window for the viral administration will be developed for translation to clinical trials.

Our treatment is being developed as a neoadjuvant regime to treat head and neck cancer patients undergoing surgical removal of primary tumours. Head and neck cancer is the 16th most common cause of cancer worldwide, responsible for 2% of all cancer cases diagnosed annually according to current information provided by CR-UK. Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancer diagnosed (90% of the 442,000 cases of head and neck cancer diagnosed worldwide in 2012). Thus, around 398,000 patients worldwide are potential end users of our regime. The standard treatment options are radical surgery to remove the primary tumour and associated lymph nodes, followed in most cases by radiotherapy to target residual disease. However, between 50-70% of patients undergoing this treatment regime will relapse and succumb to the disease within five years due to metastasis and recurrence, suggesting that in the majority of cases, post-surgical radiotherapy is ineffective at controlling progression of residual disease. The safety of oncolytic virotherapy has been well established in a number of clinical trials over the last decade and only transient 'flu-like' symptoms have been reported as side effects, compared to the more severe side effects associated with radiotherapy including extreme fatigue, nausea, bone marrow suppression and difficulties in eating and drinking. A by-product of virus-directed tumour lysis is that our regime can also result in long-term tumour-specific immunity within the patient to prevent future relapse of the primary tumour. Our research in this project will be mostly focused on head and neck cancer, but this approach could be applied to many other solid tumours.