145 Oncolytic Adenoviral Infection of Chordoma Achieves Treatment Efficacy Through Immunogenic Cell Death and Tumor Microenvironment Alteration

INTRODUCTION: Chordomas are locally aggressive neoplasms of the axial skeleton with recurrence rates approaching 40%. Moreover, recurrent chordomas are nearly impossible to eradicate—highlighting an unmet clinical need. METHODS: Using the replicating oncolytic adenovirus Delta-24-RGD, we investigate the efficacy chordoma treatment using in vitro approaches, ex vivo bone scaffolds, and in vivo murine models. Additionally, we explore the underlying mechanism of OV cytotoxicity, immunogenic cell death, Brachyury modulation, and reshaping of the TME towards a pro-inflammatory state. RESULTS: Across a panel of human chordoma cell lines, delta-24-RGD achieved viral infectivity, oncolysis and immunogenic cell death. This treatment response was similarly demonstrated in chordoma cultured in bone scaffold models. Delta-24-RGD infection was associated with concomitant Brachyury downregulation within both infected and uninfected chordoma cells in vitro, suggesting a pleiotropic effect following oncolytic viral infection. In vivo models of CH22 chordoma treated with delta-24-RGD demonstrated shrinkage in tumor volume and enhanced overall survival. Utilizing a human chordoma tissue microarray, the immunosuppressive macrophage marker CD163 was associated with shortened recurrence free survival. Using macrophage/chordoma co-culture, delta-24-RGD infection reduced macrophage expression of CD163. CONCLUSIONS: Delta-24-RGD achieves efficacy in multiple models of chordoma including mice bearing CH22 tumors. The chordoma TME is associated with clinical outcomes and delta-24-RGD infection reverses a deleterious immunosuppressive immune profile. These studies provide a framework for future clinical trial implementation for patients with metastatic or recurrent chordoma.