Translational development of oncolytic Newcastle Disease Virus for treatment of colorectal cancer

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Cancer remains an important cause of morbidity and mortality despite the refinement of techniques used to manage the disease. Interventions like chemotherapy, radiotherapy and radical surgery can take patients to the limits of tolerable side effects in order to provide a modest survival advantage, particularity in advanced carcinomas. Immunotherapy is a different approach that aims to widen the margin between efficacy and tolerability of drugs and in some patients induce a full and lasting remission. Oncolytic viruses are an interesting emerging class of therapies that utilise vaccine-like viruses to replicate selectively within and destroy cancer cells whilst simultaneously stimulating the immune system. Cancer often evades the body's own attempt to reject disease tissue, by masking the immune system from recognising any evidence of abnormal cells and processes. However, when a cancer-selective virus begins to replicate in tumour cells and destroys them through a process called lysis, the resulting pro-inflammatory environment attracts the attention of the immune system the reality of the diseased tissue can be recognised. The first example of a successful oncolytic virus cancer vaccine was approved recently for the treatment of metastatic melanoma, where the immune system, influenced by the virus was able to clear the disease in several of the patients who showed durable (and often ongoing) responses. The current proposal aims to build on this early development, using a powerful oncolytic virus vaccine (based on Newcastle Disease Virus, NDV) that should be even more capable of directing the immune system towards identifying and destroying cancer cells. Our approach will involve expressing cytokines, the messaging signals of the immune system, from the NDV oncolytic cancer vaccine in order to encourage a more robust immune response. In this way we hope to achieve efficacy in cancer indications that have have thus far been refractory to immunotherapy such as colorectal cancer. Although this project will address only the initial proof of concept stage, it will be conducted in a way that will enable future development and clinical trials. We have structured the proposal as a strong and dynamic collaboration between established research groups in Malaysia and the UK. The Malaysian partner has world class expertise, and many years practical experience, in developing oncolytic viruses based upon NDV. The UK team has already developed an oncolytic virus based on adenovirus, successfully through preclinical studies to a series of clinical trials. The partnership proposed here will combine the key expertise form both centres in fostering rapid and ethical development of oncolytic NDV through basic scientific study, through preclinical development and will position it ready to enter clinical trial for colorectal cancer. In this way we aim to use the academic and translational strengths in both centres in creating a new therapeutic for potential treatment of this devastating disease.