ANGI-11. DIRECT GLIOMA BLOOD VESSEL DISRUPTION IMPROVES IMMUNE THERAPY BUT WORSENS ANTI-VEGF THERAPY

摘要

Glioblastoma is the most vascularized and aggressive glioma with a median survival of less than 2 years. Despite promising clinical trials inhibiting vascular endothelial growth factor (VEGF) failed to improve patient survival. We used Tie2p/e LV [Tie2-TK-IRIS-GFP] mice which express the conditionally cytotoxic gene thymidine kinase (TK) under the control of endothelial-specific Tie2 promoter. Administration of gancylovir (GCV) for 7 days disrupts reactive, proliferating blood vessels within the tumor. We implanted mice with NRAS/shp53 (NP) GBM neurospheres. Three days later mice were treated with GCV to kill reactive tumor vessels. GCV prolonged survival by delaying tumor proliferation and increasing tumor necrosis. GCV administration decreased blood vessel density in the center but not in the tumor peripheral. GCV mediated blood vessel disruption resulted in tumor cell death. To further increase tumor cell death and develop anti-tumor immune responses, we used TK+Flt3L adenoviruses mediated immune therapy to increase mouse survival. We found that combination of tumor blood vessel disruption by GCV, and TK/Flt3L immune therapy, significantly extended the survival of mice compared to GCV therapy alone. Furthermore, adding radiation therapy to the GCV/TK+Flt3L immune therapy further enhanced mouse survival. We assumed that if anti-VEGF therapy effectively induces tumor blood vessel normalization then this could further increase the efficacy of TK+Flt3L therapy by increasing immune cells infiltration into the tumor. However, combining anti-VEGF therapy with TK+Flt3L did not improve survival compared to each therapy alone suggesting that blood vessel disruption may actually decrease the efficacy of anti-VEGF therapy. Our results provide evidence that combining direct tumor blood vessel disruption, and TK/Flt3L immune therapy, represents a novel therapeutic approach for the treatment of GBM. We also demonstrate that blood vessel disruption limits the anti-tumor effect of anti-VEGF therapy. This could explain the recently described failure of anti-VEGF therapy in human GBM patients.