Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy.
Date
2017-01-01Author
Ilett, E
Kottke, T
Thompson, J
Rajani, K
Zaidi, S
Evgin, L
Coffey, M
Ralph, C
Diaz, R
Pandha, H
Harrington, K
Selby, P
Bram, R
Melcher, A
Vile, R
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Th1 Cells
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Animals
Mice
Vesiculovirus
Reoviridae
Melanoma
Granulocyte-Macrophage Colony-Stimulating Factor
Immunotherapy
Oncolytic Virotherapy
Oncolytic Viruses
Th17 Cells
Melanoma-Specific Antigens
Cell Cycle Checkpoints
Research team
Targeted Therapy
Translational Immunotherapy
Language
eng
Date accepted
2016-10-04
License start date
2017-01
Citation
Gene therapy, 2017, 24 (1), pp. 21 - 30
Publisher
NATURE PUBLISHING GROUP