ATIM-03. BIOMARKER ANALYSIS SUPPORTS THE VB-111 DUAL MECHANISM OF ACTION

Abstract

BACKGROUND: VB-111 (Ofranergene Obadenovec) is non-integrating, non-replicating, Adeno 5 vector which targets the vasculature through induction of endothelial apoptosis. Our prior phase 2 study has shown a nearly doubling of overall survival (OS) in recurrent glioblastoma (rGBM) (59v32 weeks), and our pivotal phase 3 GLOBE study is fully accrued. To better understand any predictors of benefit and better define alternative mechanisms of action we assess both molecular and radiographic biomarkers of response. METHODS: Tumor volumes were determined from T1-post and FLAIR T2 weighted images, and values extracted from ROIs of ADC, MTT, standardized rCBV maps. Baseline serum and 6h post infusion underwent cytokine profiling using a luminex array. To delineate the source of cytokines orthotopic U251 tumors were treated with VB-111 or control, resected, microglia (CD11b) and T cells (CD3) sorted, and individually cocultured with activated splenocytes. RESULTS: In the univariate cox analysis, baseline srCBVs for both VB-111 and combination groups demonstrated statistically significant association with OS (p=0.0198 and p=0.0458 respectively). In the VB-111 group, post-treatment srCBV also demonstrated significant association with OS (p=0.024). Whereas, in combination group, baseline MTT is significantly associated with OS (p=0.0323). Several cytokines 6h post VB-111 infusion correlated with overall survival including IL-1Rα, IL-17α, MIP1α, and TNFα (p<0.05). When U251 tumor microglia and T cells were cocultured with splenocytes and activated with LPS (72h), several cytokines including MIP1α, MIP1β, IL-10 and RANTES were significant higher from mice administered VB-111 (p<0.05). Conversely, using CD3/CD28 for activation, a decrease in immunosuppressive cytokines was observed including IL-10, 4, 3, and 5. These results suggested that tumoral microglia are responsible for cytokine release with a profile that promotes a cytotoxic T cell response. CONCLUSION: Improved survival in VB-111 treated patients correlates with both vascular imaging parameters and cytokine response, supporting both immune and anti-angiogenic mechanisms of this anti-cancer virotherapy.