1341 Oncolytic Adenoviral Infection and Subsequent Immunogenic Cell Death Achieves Intracranial Tumor Control in Disparate Models of Melanoma Brain Metastases

INTRODUCTION: Amongst all solid cancers, melanoma brain metastases (MBM) have the highest likelihood of metastasizing to the brain. The emergence of immune checkpoint inhibitors (ICI) for metastatic melanoma have demonstrated increasingly promising results; however, intracranial progression remains a challenging obstacle. METHODS: To counteract immunosuppressive features of the tumor microenvironment (TME), a third-generation oncolytic adenovirus (Delta-24-RGDOX) has been developed which expresses the immune stimulatory OX40 ligand (OX40L). We quantified the cytotoxic capacity of Delta-24-RGDOX and its ability to achieve immunogenic cell death (ICD) in vitro along with cerebral organoid co-culture models. Additionally, we used a series of syngeneic murine melanoma models to explore local and systemic antitumor immunity following Delta-24-RGDOX infection. RESULTS: Delta-24-RGDOX inoculation achieved viral infection, OX40L cell surface expression, tumor cell cytotoxicity, and ICD in vitro. Viral oncolysis was recapitulated in a cerebral organoid melanoma co-culture model with concomitant alterations in microglia activation suggesting a viral-clearing role within the TME. Local tumor clearance was achieved in orthotopic intracranial models following direct intracranial viral inoculation alone, and in combination with ICI. Lastly, we demonstrated improvement in overall survival in a synchronous subcutaneous/intracranial B16F10 model where the subcutaneous tumor was treated with Delta-24-RGDOX in combination with ICI. CONCLUSIONS: Delta-24-RGDOX achieves viral infection, oncolysis, and ICD following infection of melanoma cell lines. These findings translated in multiple in vivo models including immune cell activation and systemic antitumor immunity against uninfected MBM. Future studies are needed to explore the role of immune cell trafficking, myeloid cell modulation, T cell priming, and clonal expansion withing locally infected and the distant melanoma TME.