Poster abstracts

Poster number 94 submitted by Luke Russell

Inhibition of CCN1 signaling as a strategy to improve the efficacy of oncolytic HSV-1 treatment for glioblastoma therapy

Luke Russell (Neurological Surgery; Ohio State University Wexner Medical Center), Amy Haseley (Neurological Surgery; Ohio State University Wexner Medical Center), Jianhua Yu (Internal Medicine; Ohio State University Wexner Medical Center), Balveen Kaur (Neurological Surgery; Ohio State University Wexner Medical Center)

Abstract:
Cysteine-rich 61 (CCN1) is a 4-domain matricellular protein that promotes angiogenesis, cell adhesion, migration, invasion, and inflammation. CCN1 is upregulated in virally infected glioma cells and is pro-inflammatory (Haseley et al. Cancer Res, 2012) both by directly and indirectly activating macrophages. CCN1 induces indirect activation by binding the α6β1 integrin receptor on glioma cells to initiate a type-1 interferon response, measured by significant upregulation of interferon response genes in CCN1 overexpressing glioma cells. Macrophage migration was directly induced by purified CCN1 protein alone, and this induction was significantly reduced using neutralizing anti-αM or β2 antibodies (P<0.05). We hypothesized that secreted CCN1, through its pro-inflammatory mechanisms, inhibits viral replication and propagation in tumors treated with oncolytic herpes simplex virus type 1 (HSV1), thereby reducing antitumor efficacy of the virus. We investigated the use of a function-blocking anti-CCN1 antibody in vivo in combination with oncolytic HSV1 to treat subcutaneous gliomas in NUDE mice. IP administration of anti-CCN1 antibody improved oncolytic HSV1 replication, measured by luciferase imaging and HSV1 staining, and reduced macrophage and NK infiltration in SQ tumors over an IgG control group. Combination anti-CCN1 antibody and oncolytic HSV1 therapy significantly improved time to progression (p=0.047) without significant enhancement in survival (p=0.10). Our results implicate CCN1 as a regulator of the antiviral innate immune response which can be partially overcome in vivo by administering a function-blocking anti-CCN1 antibody. This treatment was able to slow regrowth of tumors and is a promising indication that CCN1 blocking therapy in vivo may further enhance oncolytic viral efficacy in the treatment of glioblastoma.

Keywords: Glioblastoma, Oncolytic, Cancer