Summary

Modulation of adaptive immunity to overcome resistance to anti-angiogenic therapy by IL-17 inhibition
Angiogenesis inhibitors have evolved in the past decade as one of the most promising biology based therapeutic strategies. Pre-clinical studies (published in 1993 and 1994) provided proof of principle that blocking of VEGF dramatically inhibits tumor growth. These observations led to the successful development of inhibitors for VEGF and VEGF receptors by various pharmaceutical companies. Bevacizumab (Bev), a monoclonal antibody neutralizing VEGF, was the first-in-class drug to achieve FDA approval for the treatment of colorectal carcinoma in 2004 and later on in other cancer types, including glioblastoma. Anti-VEGF therapy led to an increase in progression free survival in recurrent and primary GBM, but its definite role in first-line-treatment is less clear. Importantly, several preclinical studies suggested that resistance to anti-angiogenic therapy might evolve in the course of the treatment due to an infiltration of specially polarized myeloid cells.
We investigated matched biopsy pairs (pre/post therapy) from 40 GBM patients treated with Bevacizumab. Matched biopsy samples were analysed by immunohistochemistry for microvascular density, pericyte coverage, hypoxia markers and for infiltrating immune cells (CD68, CD3, CD4, CD8, CD206, CSF1-R). Our results suggest that new targets are induced upon Bev-therapy, including among others, the pro-angiogenic protein Angiopoietin-2. We therefore investigated the potential role of the Tie2/Angiopoietin (Ang) signaling pathway in human and murine glioblastomas. We here show by means of 1) transgenic mice overexpressing Angiopoietin-1 (GFAPtet/Ang-1), 2) transgenic mice overexpressing Angiopoietin-2 (Tie-1tet/Ang-2), 3) application of synthetic activators of the Tie2 receptor tyrosine kinase, 4) application of peptibodies targeting Ang-1 and Ang-2 and 5) application of monoclonal antibodies blocking Ang-2, that targeting of the Tie2/Angiopoietin signaling pathway leads to vascular normalization, diminished influx of pro-tumorigenic myeloid cells and prolonged overall survival in mice pretreated with VEGF-blockers.  These findings suggest that targeting of the Tie2/Angiopoietin pathway, alone or in combination with VEGF inhibition, might be a potential therapeutic option in glioblastoma.