Combinatorial effects of VEGFR kinase inhibitor axitinib and oncolytic virotherapy in mouse and human glioblastoma stem-like cell models

Purpose: Glioblastoma (GBM), a fatal brain cancer, contains a subpopulation of GBM stem-like cells (GSCs) that contribute to resistance to current therapy. Angiogenesis also plays a key role in GBM progression. Therefore, we developed a strategy to target the complex GBM microenvironment, including GSCs and tumor vasculature. Experimental design: We evaluated the cytotoxic effects of VEFGR tyrosine kinase inhibitor (TKI) axitinib in vitro and then tested anti-tumor efficacy of axitinib in combination with oncolytic herpes simplex virus (oHSV) expressing anti-angiogenic cytokine murine IL12 (G47-mIL12) in two orthotopic GSC-derived GBM models: patientderived recurrent MGG123 GSCs, forming vascular xenografts in immune-deficient mice, and mouse 005 GSCs, forming syngeneic tumors in immune-competent mice. Results: GSCs form endothelial-like tubes and were sensitive to axitinib. G47-mIL12 significantly improved survival, as did axitinib, while dual combinations further extended survival significantly compared to single therapies alone in both models. In MGG123 tumors, axitinib was effective only at high doses (50 mg/kg), alone and in combination with G47-mIL12, and this was associated with greatly decreased vascularity, increased macrophage infiltration, extensive tumor necrosis and PDGFR/ERK pathway inhibition. In the mouse 005 model, anti-glioma activity, after single and combination therapy, was only observed in immune-competent mice and not T cell-deficient athymic mice. Interestingly, immune checkpoint inhibition did not improve efficacy. Conclusions: Systemic TKI (axitinib) beneficially combines with G47-mIL12 to enhance anti-tumor efficacy in both immune-deficient and immune-competent orthotopic Saha et al 4 GBM models. Our results support further investigation of TKIs in combination with oHSV for GBM treatment.

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