Oncolytic adenoviral infection of chordoma achieves treatment efficacy associated with immunologic response and tumor microenvironmental alteration

BACKGROUND: Chordoma is a midline neoplasm accounting for approximately 20% of primary spinal tumors. Due to chordoma's locally aggressive nature, patients experience high rates of disease progression and have limited treatment options, highlighting an unmet clinical need. This underscores the importance of exploring novel therapeutic strategies. Oncolytic viral (OV) therapy uses genetically modified viruses to selectively replicate in tumor cells, mediate tumor cell lysis, and initiate a pro-inflammatory response within the infected tumor microenvironment (TME). The aim of the study was to evaluate the anti-chordoma effect of the replicating oncolytic adenovirus Delta-24-RGD. METHODS: The efficacy of Delta-24-RGD was assessed using in vitro approaches, ex vivo bone scaffolds, and in vivo murine models. Additionally, we explored the underlying mechanism of OV cytotoxicity, immunogenic cell death (ICD), brachyury modulation, and reshaping of the TME towards a pro-inflammatory state. RESULTS: Delta-24-RGD achieved viral infectivity, oncolysis, and ICD across multiple human chordoma cell lines and ex vivo bone scaffold models. In vivo murine xenograft models of human CH22 and U-CH1 chordoma treated with Delta-24-RGD resulted in tumor volume reduction, enhanced overall survival, and microenvironmental transcriptional modulation. Analyzing a human chordoma tissue microarray, the immunosuppressive macrophage marker CD163 was associated with shortened recurrence-free survival. Using macrophage/chordoma co-culture, OV infection achieved a reduction in macrophage CD163 expression and a concomitant pro-inflammatory macrophage polarization. CONCLUSIONS: The immunosuppressive chordoma TME is associated with clinical outcomes and our data suggests OV infection reverses this deleterious immunosuppressive profile. These studies provide a framework for future clinical implementation among chordoma patients.