Reprogramming Of The Tumor Immune Microenvironment By An Ang-2/Vegf Bispecific Antibody Delays Tumor Growth And Prolongs Survival In Preclinical Gbm Models

Glioblastoma almost always recurs following standard therapy with surgery and chemoradiation. The addition of anti-VEGF therapy to the standard treatment regimen did not increase the dissatisfactory overall survival of GBM patients. Our previous clinical data suggest that anti-VEGF treatment may reduce the anti-tumor immune response. Furthermore we have previously shown that angiopoietin-2 (Ang-2) overexpression confers resistance to anti-VEGF therapy in preclinical GBM. Here we show that combined Ang-2/VEGF inhibition with a bispecific monoclonal antibody could overcome resistance to anti-VEGF treatment by modulating the anti-tumor immune response. We treated mice bearing orthotopic syngeneic GBMs or a patient-derived GBM cell line with antibodies inhibiting either VEGF (B20.4.1.1) or Ang-2/VEGF (A2V, crossmab). We examined the treatment effects on T-cell, myeloid derived suppressor cell (MDSC), microglia and macrophage populations within the tumor. We found that in both models A2V reprogrammed pro-tumor M2 macrophages towards the anti-tumor M1 phenotype. Furthermore we show that A2V also reprogrammed tumor-associated microglia towards an anti-tumor phenotype. We did not observe therapy-induced effects on other immune cell populations within the tumor. Reprogramming of the tumor immune microenvironment by A2V translated into tumor growth delay and prolonged survival in preclinical GBM models. The anti-tumor immuno-modulatory potential of dual anti-angiogenic therapy supports clinical testing of this approach for GBM patients.