The aim of this project is to enhance the efficacy of a tumour killing virus and break tolerance within the tumour to induce an immune response against the primary tumour and metastatic deposits. The proposed strategy requires three steps. First, the tumour immunological microenvironment needs to be reset as tumours utilize a variety of mechanisms to escape host immune system. Here, we propose to use the chemotherapeutic agent cyclophosphamide to temporally deplete suppressor T cells and recruit new dentritic cell progenitors. Second, to kill cancer cells, we propose to systemically deliver the potent tumour-killing (oncolytic) adenovirus ICOVIR15, which replicates selectively in cancer cells with pRB pathway mutations. In order to favour anti-tumour immunity, the ICOVIR15 will be genetically engineered to express cytokines that have been shown to be useful to stimulate anti-tumour responses such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-g). Moreover, IFN-g has also been shown to kill tumour-associated vasculature. The host group has been awarded with three “non-commercial” clinical research grants from the “Fondo de Investigaciones Sanitarias” of the Ministry of Innovation and Science of Spain to test ICOVIR5 in clinical trials. ICOVIR5 is being produced under Good Manufacturing Practices. If the novel GM-CSF or IFNg armed viruses show promising results at preclinical level, the host group will apply for other non-commercial research grants to test it in clinical trials. This project is also aimed at further developing the skills of the applicant in genetic engineering, virotherapy, immunology and working in different tumour models. The applicant would move from the UK to Spain. The applicant hopes to establish herself as an expert in the multidisciplinary areas of cancer gene therapy such as immunotherapy, angiotherapy and virotherapy.