Abstract
INTRODUCTION: DIPG is the most common malignant brainstem tumor in children. The resistance of DIPG to standard treatments along with inoperability of this tumor because of the anatomical location leave DIPG patients with dismal prognosis. Multiple studies revealed that DIPG patients have only a few months of survival after detection of cranio-spinal metastasis. Our previous work showed that a humanized anti-CD47 antibody (anti-huCD47 mAb), an immune-modulatory drug that increases phagocytic activity of macrophages against cancer cells, has a therapeutic effect on DIPG xenografts. However, the efficacy of anti-CD47 therapy was reduced with tumor size and presence of metastasis at the onset of treatment. Therefore, we tested the synergistic effect of anti-huCD47 mAb combined with anti-msCD40 mAb, another immuno-modulatory antibody that increases the recruitment of macrophages to the tumor site, on DIPG xenografts with cranio-spinal dissemination. METHODS: Human-derived DIPG cells were infected with GFP-luciferase expressing virus and injected to the pons of NOD scid gamma mice. The engraftment was verified via bioluminescent (BLI) imaging. The mice with positive signal in forebrain and spine were randomized for treatment with anti-huCD47 mAb alone, anti-msCD40 mAb alone, anti-huCD47 mAb coupled with anti-msCD40 mAb, and control. The efficacy of treatment was measured using follow-up BLI imaging and survival analysis. RESULTS: Follow-up BLI imaging revealed significant decline in the flux measures of mice receiving combined treatment (P< 0.05). BLI signals from the spinal and forebrain strongly diminished in the mice under combined treatment compared to the other groups. A significant extension in survival was seen in this group compared to the other three groups (P < 0.05). CONCLUSION: Combinatorial treatment with anti-CD47 Ab and anti-CD40 Ab is effective in the removal of not only DIPG from a primary site but also a cranio-spinal dissemination of the disease.