ICAM-1 as a biomarker of efficacy for oncolytic Coxsackievirus A21 in patient-derived Ewing sarcoma models

Ewing sarcoma (EWS) is a rare paediatric malignancy of the bone and soft tissue and requires better-tolerated and improved therapies. Oncolytic viruses (OV) preferentially replicate in cancer cells, causing oncolysis, and activate both innate and adaptive anti-tumour immunity. Thus, OV have the potential to generate long-lasting, systemic, anti-cancer activity. Using a unique panel of patient-derived EWS cultures (PDES), recently derived from patient tumours at diagnosis and relapse, we have identified oncolytic coxsackievirus A21 (CVA21) as a candidate therapeutic OV in EWS, due to its high oncolytic activity and immune stimulation. PDES, unlike established EWS cell lines, expressed intercellular adhesion molecule (ICAM-1), the CVA21 viral entry receptor, and were sensitive to CVA21-mediated oncolysis. Treatment with known ICAM-1 inducers including tumour necrosis factor (TNF), and the clinically deliverable agent all-trans retinoic acid (ATRA), increased ICAM-1 expression and enhanced CVA21-induced oncolysis. Importantly, whilst CVA21 replication and oncolysis were inhibited by antiviral type I interferon, pre-treatment with ICAM-1 inducers (or CVA21-induced immune-mediated cytokines) overcame this inhibition. In addition to direct oncolysis, co-culture of CVA21-infected PDES with PBMC stimulated significant immune-mediated killing. This study presents pre-clinical evaluation of CVA21 using clinically relevant PDES samples and identifies CVA21 as a promising candidate for EWS immunotherapy.