657. Enhancing Therapeutic Efficacy of an Oncolytic Virus with a Beta-1 Integrin Blocking Antibody, OS2966

Abstract

Glioblastoma Multiforme (GBM) is a destructive cancer of the central nervous system with poor outlook for its patients, which prompts for development of novel therapeutic approaches such as oncolytic viruses (OVs). OVs are genetically engineered viruses with tumor specific replication and lead to lysis and destruction of cancer cells. Our lab has developed a novel oncolytic Herpes Simplex Virus (oHSV), 34.5ENVE, which expresses the anti-angiogenic protein Vasculostatin. This virus has shown unparalleled antitumor efficacy against intracranial glioma in mice. OV therapy is limited by the activation and infiltration of monocytic cells that promote virus clearance and inhibit tumor destruction. β1 integrins are cell surface molecules involved in cellular proliferation, invasion and inflammation. We revealed that oHSV-induced cysteine-rich 61 protein (CCN1) binds with integrins on the surface of glioma cells and macrophages, triggering antiviral type-I interferon and chemokine responses that increase macrophage infiltration and activation, which causes increased virus clearance in glioblastoma cells and limits oncolytic virus efficacy. To improve OV therapeutic efficacy, we combined oHSV with OS2966, a β1 integrin neutralizing antibody, which has been humanized in anticipation of clinical trials. We hypothesized that OS2966 would mitigate CCN1- β1 integrin induced inflammation and increase oHSV replication. Combination treatment with OS2966 increased oHSV replication and glioma cell killing. Migration assays revealed that treatment with OS2966 strongly inhibited oHSV-induced raw246.7 macrophage cell migration toward infected glioblastoma cells. From our results, we demonstrate that β1 integrins limit oHSV replication. Furthermore, we concluded that OS2966 could rescue CCN1- β1 integrin mediated macrophage and microglia migration toward oHSV infected GBM cells. Our findings show how a β1 integrin neutralizing antibody (OS2966) inhibits the innate immune response triggered upon oHSV treatment. This work suggests that β1 integrin inhibition may be utilized in the development of a novel oHSV therapeutic strategy.