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 (IV) 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.
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Timothy
T
Kottke
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Feorillo
F
Galivo
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Phonphimon
P
Wongthida
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Rosa
R
Maria Diaz
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Jill
J
Thompson
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
Dragan
D
Jevremovic
Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida, USA.
Glen N
GN
Barber
Cancer Research UK Clinical Centre, Leeds Teaching Hospitals NHS Trust, University of Leeds, St. James's University Hospital, Leeds, UK; Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
Geoff
G
Hall
Cancer Research UK Clinical Centre, Leeds Teaching Hospitals NHS Trust, University of Leeds, St. James's University Hospital, Leeds, UK; Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
John
J
Chester
Cancer Research UK Clinical Centre, Leeds Teaching Hospitals NHS Trust, University of Leeds, St. James's University Hospital, Leeds, UK; Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
Peter
P
Selby
The Institute of Cancer Research, London, UK.
Kevin
K
Harrington
Cancer Research UK Clinical Centre, Leeds Teaching Hospitals NHS Trust, University of Leeds, St. James's University Hospital, Leeds, UK; Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
Alan
A
Melcher
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; Cancer Research UK Clinical Centre, Leeds Teaching Hospitals NHS Trust, University of Leeds, St. James's University Hospital, Leeds, UK; Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK; Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. Electronic address: vile.richard@mayo.edu.
Richard G
RG
Vile