Immunogenic HSV-mediated Oncolysis Shapes the Antitumor Immune Response and Contributes to Therapeutic Efficacy

Abstract

Within the oncolytic virus field, the extent of virus replication that is essential for immune stimulation to control tumor growth remains unresolved. Using infected cell protein 0 (ICP0)-defective oncolytic Herpes simplex virus type 1 (HSV-1) and HSV-2 viruses (dICP0 and dNLS) that show differences in their in vitro replication and cytotoxicity, we investigated the inherent features of oncolytic HSV viruses that are required for potent antitumor activity. In vitro, the HSV-2 vectors showed rapid cytotoxicity despite lower viral burst sizes compared to HSV-1 vectors. In vivo, although both of the dICP0 vectors initially replicated to a similar level, HSV-1 dICP0 was rapidly cleared from the tumors. In spite of this rapid clearance, HSV-1 dICP0 treatment conferred significant survival benefit. HSV-1 dICP0-treated tumors showed significantly higher levels of danger-associated molecular patterns that correlated with higher numbers of antigen-presenting cells within the tumor and increased antigen-specific CD8+ T-cell levels in the peripheral blood. This study suggests that, at least in the context of oncolytic HSV, the initial stages of immunogenic virus replication leading to activation of antitumor immunity are more important than persistence of a replicating virus within the tumor. This knowledge provides important insight for the design of therapeutically successful oncolytic viruses.

Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia

“…For some viruses (eg, T-vec, reovirus), this antitumor immune response can sometimes be more important than that of direct oncolysis where direct injection of the primary tumor is associated with regression of distant nodules. [28][29][30][31] Although cancer cells express tumor antigens, spontaneous rejection of tumors by cytotoxic CD8…”

Dual silencing of Bcl-2 and Survivin by HSV-1 vector shows better antitumor efficacy in higher PKR phosphorylation tumor cells in vitro and in vivo

“…1 Conventional chemotherapy and radiotherapy achieve limited efficacies leading to the search for novel ways to treat cancer. 2 Oncolytic viruses selectively propagate in cancer cells while displaying minimal adverse effects in healthy cells, making it one of the most promising treatments. 3 For example, oncolytic herpes simplex virus type-1 (HSV-1) vector is a useful tool for treating solid malignant tumors.…”

Genome-wide lentiviral shRNA screen identifies serine/arginine-rich splicing factor 2 as a determinant of oncolytic virus activity in breast cancer cells

“…4 Studies in preclinical murine tumor models showed that the antitumor activity of the prototype HSV-1 ICP0-null OV KM100 depends on whether the tumor model is tolerized. 4,6 Although in vitro tumor cell cytotoxicity mirrors the in vivo therapeutic efficacy of some OVs, 7 we fail to observe a similar correlation with our herpesvirus-based OVs, 5,6,8 despite the requirement for replication of competent vectors. 4 Thus, the complex molecular interactions that dictate permissivity of oncolytic HSVs in cancer cells remain elusive.…”

“…3 We have developed and tested the efficacy of HSV-1 deleted for the viral protein ICP0 as oncolytic vectors. [4][5][6] These OVs show modest in vitro oncolysis mainly in cancer cell types with impaired abilities to mount anti-viral responses. 4 Studies in preclinical murine tumor models showed that the antitumor activity of the prototype HSV-1 ICP0-null OV KM100 depends on whether the tumor model is tolerized.…”