title: Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy.
abstract: The anti-tumour effects associated with oncolytic virus therapy are mediated significantly through immune-mediated mechanisms, which depend both on the type of virus and the route of delivery. Here, we show that intra-tumoral oncolysis by Reovirus induced the priming of a CD8+, Th1-type anti-tumour response. By contrast, systemically delivered Vesicular Stomatitis Virus expressing a cDNA library of melanoma antigens (VSV-ASMEL) promoted a potent anti-tumour CD4+ Th17 response. Therefore, we hypothesised that combining the Reovirus-induced CD8+ T cell response, with the VSV-ASMEL CD4+ Th17 helper response, would produce enhanced anti-tumour activity. Consistent with this, priming with intra-tumoral Reovirus, followed by an intra-venous VSV-ASMEL Th17 boost, significantly improved survival of mice bearing established subcutaneous B16 melanoma tumours. We also show that combination of either therapy alone with anti-PD-1 immune checkpoint blockade augmented both the Th1 response induced by systemically delivered Reovirus in combination with GM-CSF, and also the Th17 response induced by VSV-ASMEL. Significantly, anti-PD-1 also uncovered an anti-tumour Th1 response following VSV-ASMEL treatment that was not seen in the absence of checkpoint blockade. Finally, the combination of all three treatments (priming with systemically delivered Reovirus, followed by double boosting with systemic VSV-ASMEL and anti-PD-1) significantly enhanced survival, with long-term cures, compared to any individual, or double, combination therapies, associated with strong Th1 and Th17 responses to tumour antigens. Our data show that it is possible to generate fully systemic, highly effective anti-tumour immunovirotherapy by combining oncolytic viruses, along with immune checkpoint blockade, to induce complementary mechanisms of anti-tumour immune responses.
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.|Leeds Institute of Cancer and Pathology, St James' University Hospital, Leeds, UK.
authors: E
authors: E
authors: Ilett
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors: T
authors: T
authors: Kottke
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors: J
authors: J
authors: Thompson
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors: K
authors: K
authors: Rajani
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.|The Institute of Cancer Research, London, UK.
authors: S
authors: S
authors: Zaidi
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors: L
authors: L
authors: Evgin
authors: Oncolytics Biotech Incorporated, Calgary, Canada.
authors: M
authors: M
authors: Coffey
authors: Leeds Institute of Cancer and Pathology, St James' University Hospital, Leeds, UK.
authors: C
authors: C
authors: Ralph
authors: Vyriad, Rochester, MN.
authors: R
authors: R
authors: Diaz
authors: University of Surrey, Guildford, UK.
authors: H
authors: H
authors: Pandha
authors: The Institute of Cancer Research, London, UK.
authors: K
authors: K
authors: Harrington
authors: Leeds Institute of Cancer and Pathology, St James' University Hospital, Leeds, UK.
authors: P
authors: P
authors: Selby
authors: Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors: R
authors: R
authors: Bram
authors: Leeds Institute of Cancer and Pathology, St James' University Hospital, Leeds, UK.
authors: A
authors: A
authors: Melcher
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.|Leeds Institute of Cancer and Pathology, St James' University Hospital, Leeds, UK.|Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors: R
authors: R
authors: Vile
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D008545:Melanoma / Q000628:therapy*; D058950:Melanoma-Specific Antigens / Q000235:genetics / Q000276:immunology; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology*; D012087:Reoviridae / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D018116:Vesiculovirus / Q000235:genetics / Q000276:immunology
chemical_list: D058950:Melanoma-Specific Antigens; D016178:Granulocyte-Macrophage Colony-Stimulating Factor