Abstract
Oncolytic viruses (OVs) are an emerging cancer therapeutic, with a near complete absence of serious adverse effects. However, clinical efficacy is relatively modest, related to poor tumor penetration, failure to lyse cancer stem cells (CSCs) and blockade of immunogenic cell death by the immunosuppressive tumor microenvironment. To overcome such limitations, we developed an OV (known as ΔPK) with multimodal anti-tumor activity. ΔPK has potent anti-tumor activity both in melanoma cell lines and xenograft animal models, associated with virus replication and the induction of multiple independent programmed cell death pathways. It lyses CSCs through autophagy modulation and it reverses the immunosuppressive tumor microenvironment by altering the balance of cytokines secreted by the tumor cells. This includes decreased tumor cell secretion of the immunosuppressive and procancerous cytokines IL-10 and IL-18 and concomitant increased secretion of the proinflammatory cytokines TNF-α, GM-CSF, IL-6 and IL-1β. ΔPK also upregulates the NKG2D ligand, MICA expressed by cytotoxic NK and T cells, and downregulates the negative immune checkpoint regulator cytotoxic T-lymphocyte antigen-4 (CTLA-4). ΔPK is well tolerated in human patients in whom it also alters the Th1/Th2 balance. Further studies are designed to elucidate the role of these contributions in different tumor types.