Abstract
Oesophageal cancer – of which adenocarcinoma (OAC) is the predominant type in the UK - is a highly aggressive malignancy, with 5-year survival rates of approximately 15%. Surgically resectable disease is treated with perioperative chemo+/-radiotherapy. Neoadjuvant chemoradiotherapy is known to improve survival, mechanistically this may occur through the induction of an anti-tumour immune response within the tumour microenvironment (TME). While chemoradiotherapy may modulate the TME towards tumour rejection, they are unselective treatments with significant systemic toxicity. Hence novel approaches to the treatment of OAC are required. Immunotherapy has achieved more precise immunomodulation with delivery of biological agents in several cancers including OAC. Most immunotherapy trials in OAC have looked at utilising immune checkpoint blockade (ICB), alone or in combination with standard treatments. Intratumoural delivery of immunotherapy provides an innovative option in the treatment paradigm, using the cancer as a vaccine against itself. The ideal combination intratumoural immunotherapy starts with a stress on the tumour, such as an oncolytic virus (OV) that triggers immunogenic cell death (ICD) followed by secondary agents that enhance antigen presentation and the activation of effector immune cells.
This Medical Research Council funded PhD has used bioinformatic analysis of the TCGA-ESCA database in combination with nine-colour multispectral immunohistochemistry, performed on a local cohort of treatment naïve OAC tumours, to gain insights into the immune tumour microenvironment of OAC, with a specific focus on the activity of natural killer and dendritic cells. Then using two 3D ex vivo tumour modelling techniques, organotypic slice culture and tumour organoids, the ability for an oncolytic HSV-1 to selectively infect, replicate within and then kill tumour tissue has been assessed. Following this the development of a novel subcutaneous immunocompetent mouse model of OAC has been successfully achieved, allowing for assessment of our combination of oncolytic virus and immunotherapies in vivo.