Treg depletion-enhanced IL-2 treatment facilitates therapy of established tumors using systemically delivered oncolytic virus.
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.
Kottke
Timothy
T
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Galivo
Feorillo
F
Wongthida
Phonphimon
P
Diaz
Rosa Maria
RM
Thompson
Jill
J
Jevremovic
Dragan
D
Barber
Glen N
GN
Hall
Geoff
G
Chester
John
J
Selby
Peter
P
Harrington
Kevin
K
Melcher
Alan
A
Vile
Richard G
RG
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
D007376:Interleukin-2