Combination Of The Anti-Angiogenic Adnectin (Tm) Bms-844203 (Ct-322) And Temozolomide Provides A Survival Advantage In An Intracanial Glioblastoma Model

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO INTRODUCTION: Despite surgery, radiation, and chemotherapy, the 14.6 month median survival of glioblastoma multiforme (GBM) patients reflects several important challenges including infiltrative malignant cells, natural resistance to apoptosis, and morphologic and genetic differences. Combination therapy may inhibit several disease processes simultaneously by preventing the development of acquired resistance, while minimizing toxicity to normal brain. Various anti-angiogenic therapies are currently under clinical investigation to assess their added benefit to standard of care therapy. These efforts are supported by preclinical evidence whereby anti-angiogenic agents can selectively prune tumor vasculature and enhance the anti-proliferative properties of chemotherapy agents. We tested BMS-844203 (CT-322; Adnexus, a BMS R&D Co), a novel neutralizing AdnectinTM directed specifically against vascular endothelial growth factor receptor-2, in combination with temozolomide (TMZ) in an established glioma in vivo model. METHODS: Fifty thousand U87vIII-ffluc cells (human GBM cell line expressing firefly luciferase) were intracranially implanted in 24 adult NOD SCID mice. Bioluminescence imaging (BLI) was used at randomization and biweekly timepoints to follow tumor size. Mice were randomized into vehicle control (Phosphate Buffered Saline (PBS)), TMZ (34mg/kg QD x 5 days), CT-322 (60mg/kg x 3 times per week) and Combination (CT-322 + TMZ) groups of 6 mice. MR imaging was used to characterize treatment effects in select mice. Animals were followed for survival and sacrificed at the first sign of morbidity. A second set of 24 mice were sacrificed for histological analysis at day 7 or 14. Immunohistochemical (IHC) staining against CD31, Ki67 or cleaved-caspase 3 was performed on paraffin-embedded brain tissue sections. RESULTS: Day 13 mean BLI values (photons/sec x 106) increased by 36,400 (PBS), 178.80 (CT-322), 61.75 (TMZ), and 6.46 (CT-322 + TMZ) fold per group. T1 post-contrast MR volumes correlated with BLI. Mean survival was 19, 29, 32, and 47 days for PBS, CT-322, TMZ, and (CT-322 + TMZ) respectively. Day 14 IHC analysis demonstrated strongly reduced blood vessel formation in CT-322 and (CT-322 + TMZ) compared to TMZ or PBS groups as demonstrated by CD31 staining. Ki67 expression was significantly reduced under CT-322, TMZ, and (CT-322 + TMZ) treatments compared to PBS control. Enhanced detection of cleaved-caspase 3 was observed in all treatment groups compared to control. Day 14 IHC results were representative of Day 7. CONCLUSIONS: The survival benefit of a combinatorial treatment using CT-322 and TMZ was superior to that of either agent alone. Tumor burden (BLI, MRI) and IHC analysis suggest that tumor growth suppression plus antiangiogenic effects may underlie the observed enhanced survival of the combo treatment. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-286.