Metastatic (stage 4) colorectal cancer (mCRC) is an almost uniformly lethal disease with only a 14% 5-year survival rate. Current treatment strategies for mCRC are limited and escape form therapeutic control is common. Development of new treatment strategies is therefore imperative. Oncolytic viruses (OVs) are attractive therapeutics for cancer as they not only kill the tumour cells by direct lysis but also act through multiple other mechanisms, simultaneously targeting several molecular pathways involved in carcinogenesis. Of great importance is their ability to induce long-lasting tumour-specific immunity to prevent recurrence of disease. Although clinical trials with various OVs have produced evidence of response, many have ultimately disappointed. Vaccinia virus (VV) has several features that make it a promising therapeutic agent. These viruses can target treatment resistant fractions of tumours, collapse tumour blood supply, cause direct tumour cell death and activate powerful immune responses in the TME. Over the past decade, we have developed a novel and effective oncolytic VV termed VacV002-TD-IL10D-ENPP1\. Most OVs must be injected directly into the tumour for therapeutic effect, but we have engineered this virus with an enhanced capacity for systemic application and we have demonstrated that therapeutically effective doses of this virus can specifically localize to the tumour after intravenous delivery. VacV002-TD-IL10D-ENPP1 has also been modified to significantly enhance the innate ability of VV to activate anti-tumour immune responses. Furthermore, we have demonstrated powerful synergy of our new VV vectors with immune checkpoint inhibition (ICI), a mode of immune therapy that is currently only effective in a small subset of mCRC patients. Here we propose to complete a pre-clinical efficacy and safety package for VacV002-TD-IL10D-ENPP1 that will provide an effective therapeutic regime for treatment of mCRC patients. To support this work, VacV Biotherapeutics will collaborate with the Cell and Gene Therapy Catapult (CGTC) who will assist with project gap analysis, market analysis and regulatory pathway review. This will allow us to collect all necessary data to support initiation of phase I clinical trials in mCRC patients in the near future. It will also promote the growth of VacV Biotherapeutics, by attracting series A investment that will support first-in-human trials of VacV002-TD-IL10D-ENPP1\.