Development of an effective therapeutic regimen for treatment of advanced pancreatic cancer using a novel immunotherapeutic agent

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumour types, with an extremely poor prognosis. It is the 7th most common cause of cancer death worldwide and the five-year survival rate remains consistently low at 3%. Without active treatment, patients with metastatic PDAC have a mean survival of 3-5 months. Even following potential curative resection, more than 80% of patients ultimately die of the disease due to local recurrence and/or distant metastasis. Current advances in surgical, adjuvant and palliative treatments have failed to improve the overall survival rate since the 1970s. Thus, new treatment strategies that are not cross-resistant with conventional chemotherapy-based regimes are imperative. A major barrier to the effective treatment of PDAC is the inaccessibility of the tumour to treatment. Furthermore, patients usually present with advanced disease that has metastasised to distant sites.Tumour-targeting oncolytic viruses (TOVs) are a new class of therapeutic that are showing immense promise in clinical trials for a number of different cancers and provide a promising platform for development of curative therapies for PDAC. TOVs not only kill the tumour cells by direct lysis but also act through multiple other mechanisms of action by targeting molecular pathways involved in carcinogenesis, as well as breaking down the immuno-suppressive tumour microenvironment and inducing a long-lasting tumour-specific immunity. Furthermore, TOVs can specifically deliver therapeutic proteins into tumours at increasing levels following viral replication within the malignant cells. Although clinical trials with various TOVs have produced evidence of response, many have ultimately disappointed, especially for PDAC. Vaccinia virus (VV) has several features that make it a promising therapeutic agent, especially since one such virus (JX594) has recently been shown to target tumours effectively after intravenous infusion, making VV an ideal TOV for treatment of inaccessible tumours such as pancreatic cancer. We have recently identified the European vaccine strain Lister vaccinia virus is an attractive platform for development of new generation of oncolytic VV for cancer treatment, especially for PDAC. Based on the lister strain, we recently developed a new generation of VV (VVTKN1L, a patent filed by QMUL Innovation Ltd), which is more tumour-specific and results in an improved antitumour efficacy. Furthermore, we have created a set of VVTKN1L vectors expressing immunomodulatory genes including VV-IL10, VV-GMCSF, VV-IL12, VV-IL15/IL15R and VV-IL-21. VVTKN1L-IL21 has demonstrated the highest therapeutic index for treatment of peritoneally disseminated pancreatic cancer. In this project we will develop an optimised therapeutic regimen by combining our novel virus with a new tumour targeted drug that regulates host immune responses as well as conventional chemotherapy (gemcitabine) for treatment of advanced pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to locally advanced and metastatic disease, and new treatment strategies are clearly imperative. Tumour-targeted oncolytic viruses (TOVs) are attractive therapeutics for cancer. TOVs not only kill the tumour cells by direct lysis but also act through multiple other mechanisms of action by targeting molecular pathways involved in carcinogenesis, as well as breaking down the immuno-suppressive tumour microenvironment and inducing a long-lasting tumour-specific immunity. Furthermore, TOVs can specifically deliver therapeutic proteins into tumours at increasing levels following viral replication within the malignant cells. Although clinical trials with various TOVs have produced evidence of response, many have ultimately disappointed, especially for PDAC. Vaccinia virus (VV) has several features that make it a promising therapeutic agent, especially since one such virus (JX594) has recently been shown to target tumours effectively after intravenous infusion, making VV an ideal TOV for treatment of inaccessible tumours such as pancreatic cancer. We have recently developed a new generation of VV (VVTKN1L, a patent filed by QMUL Innovation Ltd), which is more tumour-specific and results in an improved antitumour efficacy. Based on this new platform, we have created a set of VVTKN1L vectors expressing immunomodulatory genes including VV-IL10, VV-GMCSF, VV-IL12, VV-IL15/IL15R and VV-IL-21. VVTKN1L-IL21 has demonstrated the highest therapeutic index for treatment of peritoneally disseminated pancreatic cancer. In addition, we also found that a PI3K delta inhibitor can dramatically enhance infection of PDAC tumours after intravenous delivery of VV. In this project we are among to develop an optimised therapeutic regimen by combining our novel virus with the PI3K inhibitor and conventional chemotherapy (gemcitabine).

This project is designed to develop an effective regimen to treat the advanced pancreatic cancer patients. Figures provided by CR-UK estimate that worldwide, 338,000 people were diagnosed with PDAC in 2012, with 330,000 deaths occurring in the same period. In the UK alone it is the 5th most common cause of cancer, resulting in around 8,700 deaths each year. In most cases, surgery to remove disease is not possible due to late diagnosis. Chemotherapy is the only treatment option for these patients and usually only provides palliation. Even when the primary tumour can be removed, local recurrence occurs within 1 year in 50-80% of cases. Our novel therapeutic can be used in both settings. Firstly, as a neoadjuvant to surgery of resectable tumours to prevent recurrence due to residual disease and post-operative immune dysfunction. Secondly, as a non-cross-resistant adjuvant to the current chemotherapeutic treatments for advanced disease. In both cases, the virus can mount a direct lytic attack on the primary tumour and also break down the immune suppressive environment within the tumour site to stimulate the induction of long term anti-tumour immunity. Thus, all patients diagnosed with early or late stage disease, who currently have extremely limited treatment options, are potential end users of this regime.
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 pancreatic cancer, but this approach could be applied to many other solid tumours.