Combination of Oncolytic Herpes Simplex Viruses Armed with Angiostatin and IL-12 Enhances Antitumor Efficacy in Human Glioblastoma Models

Abstract

Oncolytic herpes simplex virus (oHSV) can potentially spread throughout the tumor, reach isolated infiltrating cells, kill them, and deliver anticancer agents. However, the host responds to oHSV by inducing intratumoral infiltration of macrophages that can engulf the virus, limiting the potential of this therapeutic strategy. Hypervascularity is a pathognomonic feature of glioblastoma (GBM) and is a promising therapeutic target. Antiangiogenic treatments have multiple benefits, including the capacity to increase oHSV efficacy by suppressing macrophage extravasation and infiltration into the tumor. Angiostatin is an antiangiogenic polypeptide, and interleukin-12 (IL-12) is an immunostimulatory cytokine with strong antiangiogenic effects. Clinical use of each has been limited by delivery issues and systemic toxicity. We tested a combination treatment strategy using oHSVs expressing angiostatin (G47Δ-mAngio) and IL-12 (G47Δ-mIL12) in two orthotopic human GBM models. Intratumoral injection of G47Δ-mAngio and G47Δ-mIL12 in mice bearing intracranial U87 or tumors derived from glioblastoma stem cells significantly prolonged survival compared to each armed oHSV alone. This was associated with increased antiangiogenesis and virus spread and decreased macrophages. These data support the paradigm of using oHSV expressing different antiangiogenic agents and show for the first time that oHSVs expressing angiostatin and IL-12 can improve efficacy in human GBM models.

Single agent efficacy of the VEGFR kinase inhibitor axitinib in preclinical models of glioblastoma

“…We chose MGG4 because this GSC line generates hypervascular and hypoxic tumors [28, 30, 35], and thus provides a useful model to investigate anti-angiogenic strategies [36]. Athymic mice bearing intracranial MGG4 tumors were treated with either axitinib or vehicle solution, and animals followed for survival.…”

“…In the commonly used U87 model, daily axitinib treatment prominently reduced tumor-associated microvascular density and prolonged survival. The MGG4 GSC-derived tumor model displays frequent abnormally dilated and tortious blood vessels and intratumoral hemorrhages, a vascular hallmark of human GBM [28, 30, 36]. CD34 endothelium staining revealed axitinib-mediated anti-angiogenic effects in the MGG4 and 005 models as well.…”

Antiangiogenic compounds: well-established drugs versus emerging natural molecules

“…Angiostatin is polypeptide that occur naturally in various animal species, including humans. It is classified as endogenous angiogenesis inhibitor and your capacity is related with downregulating VEGF expression blocking one the major vascular growth factors [80,81]. Like angiostatin, endostatin is also a polypeptide.…”

Exploring the antitumor effect of virus in malignant glioma

“…These provide the rationale for translating similar combinations to the clinic. OHSV armed with antiangiogenic transgenes like angiostatin (inhibitor of angiogenesis; G47Δ-mAngio) or the immunomodulatory IL-12 (G47Δ-mIL12) were significantly better than unarmed oHSV, while the combination of the two armed vectors further improved efficacy in vivo (39). In the immunocompetent 005 GSC model, oHSV G47Δ was insufficient alone, however, expression of IL12 (G47Δ-mIL12) significantly improved efficacy, by at least three distinct mechanisms: direct oncolysis of GSCs, anti-angiogenic effects, and T-cell mediated anti-tumor immune responses (32).…”