title: Treg depletion-enhanced IL-2 treatment facilitates therapy of established tumors using systemically delivered oncolytic virus.
abstract: There are several roadblocks that hinder systemic delivery of oncolytic viruses to the sites of metastatic disease. These include the tumor vasculature, which provides a physical barrier to tumor-specific virus extravasation. Although interleukin-2 (IL-2) has been used in antitumor therapy, it is associated with endothelial cell injury, leading to vascular leak syndrome (VLS). Here, we demonstrate that IL-2-mediated VLS, accentuated by depletion of regulatory T cells (Treg), facilitates localization of intravenously (i.v.) delivered oncolytic virus into established tumors in immune-competent mice. IL-2, in association with Treg depletion, generates "hyperactivated" natural killer (NK) cells, possessing antitumor activity and secreting factors that facilitate virus spread/replication throughout the tumor by disrupting the tumor architecture. As a result, the combination of Treg depletion/IL-2 and systemic oncolytic virotherapy was found to be significantly more therapeutic against established disease than either treatment alone. These data demonstrate that it is possible to combine biological therapy with oncolytic virotherapy to generate systemic therapy against established tumors.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Kottke
authors.forename: Feorillo
authors.initials: F
authors.lastname: Galivo
authors.forename: Phonphimon
authors.initials: P
authors.lastname: Wongthida
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Diaz
authors.forename: Jill
authors.initials: J
authors.lastname: Thompson
authors.forename: Dragan
authors.initials: D
authors.lastname: Jevremovic
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.forename: Geoff
authors.initials: G
authors.lastname: Hall
authors.forename: John
authors.initials: J
authors.lastname: Chester
authors.forename: Peter
authors.initials: P
authors.lastname: Selby
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.forename: Alan
authors.initials: A
authors.lastname: Melcher
authors.forename: Richard G
authors.initials: RG
authors.lastname: Vile
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D004730:Endothelium, Vascular / Q000187:drug effects; D007376:Interleukin-2 / Q000627:therapeutic use* / Q000633:toxicity; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000187:drug effects / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D053586:Virus Internalization; D014779:Virus Replication / Q000187:drug effects
chemical_list: D007376:Interleukin-2