1047 Preoperative Stereotactic Radiosurgery Positively Modulates the Tumor Immune Microenvironment in Glioblastoma: Preliminary Findings of a Phase I/IIa Human Clinical Trial

INTRODUCTION: Glioblastoma (GBM) is the most common and aggressive primary brain cancer, with a median overall survival of 14.6 months. The standard of care (SOC) has remained unchanged for nearly two decades, comprising supramarginal resection followed by postoperative fractionated radiotherapy and concomitant temozolomide. Despite significant resources invested to advance the field, alternatives are limited, calling for a much-needed paradigm shift. While Stereotactic Radiosurgery (SRS) is commonly utilized for other cancer types, its impact on GBM has not been thoroughly investigated. METHODS: Leveraging our ongoing phase I/IIa human clinical trial, "The NeoGlioma Study" (NCT05030298), we collected peripheral blood samples at 4 timepoints and GBM tissue from patients undergoing preoperative SRS vs SOC. We used Akoya Multiplex Staining to compare SOC and SRS-treated groups and performed RNAseq analysis on biopsied tissue pre- and post-SRS. Additionally, we conducted CyTOF analysis on peripheral blood samples longitudinally for patients in the preoperative SRS arm. RESULTS: Tissue analysis showed higher CD4:CD8 ratio, associated with better adjuvant therapy response, as well as higher M1- and lower M2-macrophage populations in PreOperative SRS vs SOC, this last known to be significant contributor to disease progression, immunosuppression, and treatment resistance. GSEA revealed enrichment of G2M checkpoint (FDR=0.001) and E2F (FDR=0.003) pathways post-SRS, associated with improved immune infiltration and radiosensitivity. Longitudinal analysis indicated increased systemic CD4 T cells post-SRS, with reduced monocytes and dendritic cells. Preoperative SRS appears to enhance both local and systemic immune activation in GBM patients, potentially improving treatment response. CONCLUSIONS: This human study highlights preoperative SRS as an innovative approach to revolutionize GBM therapy by modulating the tumor immune microenvironment towards a less aggressive profile, potentially sensitizing the cells to adjuvant chemoradiation.