Pre-clinical development for IND application of a novel systemically deliverable oncolytic Vaccinia virus for treatment of pancreatic cancer

Lead Research Organisation: Queen Mary, University of London
Department Name: Barts Cancer Institute

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is an almost uniformly lethal disease. In the UK alone, 10,000 cases are reported each year and the incidence rates are expected to rise by a further 6% by 2035. While a number of cancers are responding favourably to new immunotherapeutic treatment protocols, including vaccination and checkpoint blockade, these strategies have failed to impact PDAC survival rates, because PDAC is potently able to prevent the host immune system controlling cancer progression. Thus, there is an urgent need to design new types of therapy to overcome the barriers to conventional therapy in PDAC.

We have developed novel tumour-targeting oncolytic viruses (TOVs), which are attractive therapeutic options for cancer. These agents can, through selective replication in the tumour tissue, amplify the input dose and kill tumours by multiple mechanisms, including direct cell killing and importantly by induction of systemic anti-tumour immune responses in the patient that can target primary tumour, metastatic deposits and prevent recurrence. In addition, TOVs can act as delivery vectors, delivering immune stimulants to amplify the immune response against tumour-specific antigens that are expressed only by tumour cells, allowing the immune system to specifically recognise and kill tumour cells.

We have recently developed a new generation of TOVs called VVL-21. This new biological therapeutic agent can inflame the tumour micro-environment, promoting infiltration of multiple immune cells within pancreatic tumours. Strikingly this new agent can boost the efficacy of an approved immunotherapy agent anti-PD1 and together these agents provide a powerful therapeutic platform for treatment of pancreatic cancer. Additionally, our new therapeutic agent can be injected intravenously,which will allow targeting of metastatic cancers. These are currently targeted inefficiently by TOVs as most clinically advanced TOVs must be delivered intra-tumourally to achieve therapeutic benefit.

In this project, we aim to to achieve sufficient experimental data, including large scale manufacture of the virus to GMP standard and toxicity testing in order to get an approval by the MHRA for a Phase I clinical trial of this novel virus to treat pancreatic cancer, providing hope for improved prognosis for pancreatic cancer patients.

Technical Summary

Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic and locally advanced 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 effectively target tumours after intravenous infusion, making VV an ideal TOV for treatment of inaccessible tumours such as pancreatic cancer. We recently have developed a novel and powerful oncolytic VV which is systemically deliverable, shows improved intra- and inter-tumoral spread and has a potent ability to activate anti-tumour immune responses, providing a robust therapeutic success in several in vivo models of PDAC. Furthermore, we have demonstrated powerful synergy of the virus with immune checkpoint inhibition, a mode of immune therapy to which pancreatic cancer is characteristically unresponsive. Here we propose to complete a pre-clinical package that further demonstrates efficacy and safety, scale up vector production at GMP standard, deliver a pre-clincial toxicity package and submit an IND application for our therapy, prior to initiation of phase I clinical trials.
 
Description Evaluation of Biodistribution of VacV001 (VV-hIL21) in Syrian hamster tumour models 
Organisation Zhengzhou University
Department Academy of Medical Sciences
Country China 
Sector Academic/University 
PI Contribution I designed the experiments and provided the reagent.
Collaborator Contribution Established subcutaneous pancreatic cancer in Syrian hamster and evaluated the effect of our new virus expressing human IL-21 as human IL-21 functions in Syrian Hamster, but not in mouse.
Impact The data from this collaboration have been reported to the MRC. We jointly published several papers from our long-term collaborations (started in 2006). The collaboration is definitely multi-disciplinary, involved in virology, immunology, pathology and oncology etc.
Start Year 2015