title: The oncolytic virus ΔPK has multimodal anti-tumor activity.
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.
authors.affiliation: Department of Microbiology and Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA laurelian@som.umaryland.edu.
authors.forename: Laure
authors.initials: L
authors.lastname: Aurelian
authors.affiliation: Department of Microbiology and Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bollino
authors.affiliation: Department of Microbiology and Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Aric
authors.initials: A
authors.lastname: Colunga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D056747:Immunomodulation / Q000235:genetics; D007167:Immunotherapy; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics*; D015398:Signal Transduction; D019076:Transgenes; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology; D014779:Virus Replication
chemical_list: D002352:Carrier Proteins; D011494:Protein Kinases
keywords: HSV; MICA; immunogenic cell death; inflammatory cytokines; melanoma; oncolytic virotherapy