Smac mimetics and oncolytic viruses synergize in driving anticancer T-cell responses through complementary mechanisms

Dae-Sun Kim, Himika Dastidar, Chunfen Zhang, Franz J. Zemp, Keith Lau, Matthias Ernst, Andrea Rakic, Saif Sikdar, Jahanara Rajwani, Victor Naumenko, Dale R. Balce, Ben W. Ewanchuk, Pankaj Tailor, Robin M. Yates, Craig Jenne, Chris Gafuik and Douglas J. Mahoney ()
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Dae-Sun Kim: Alberta Children’s Hospital Research Institute
Himika Dastidar: Alberta Children’s Hospital Research Institute
Chunfen Zhang: Alberta Children’s Hospital Research Institute
Franz J. Zemp: Alberta Children’s Hospital Research Institute
Keith Lau: Alberta Children’s Hospital Research Institute
Matthias Ernst: Alberta Children’s Hospital Research Institute
Andrea Rakic: Alberta Children’s Hospital Research Institute
Saif Sikdar: Alberta Children’s Hospital Research Institute
Jahanara Rajwani: Alberta Children’s Hospital Research Institute
Victor Naumenko: Alberta Children’s Hospital Research Institute
Dale R. Balce: University of Calgary
Ben W. Ewanchuk: University of Calgary
Pankaj Tailor: University of Calgary
Robin M. Yates: University of Calgary
Craig Jenne: University of Calgary
Chris Gafuik: Alberta Children’s Hospital Research Institute
Douglas J. Mahoney: Alberta Children’s Hospital Research Institute

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Second mitochondrial activator of caspase (Smac)-mimetic compounds and oncolytic viruses were developed to kill cancer cells directly. However, Smac-mimetic compound and oncolytic virus therapies also modulate host immune responses in ways we hypothesized would complement one another in promoting anticancer T-cell immunity. We show that Smac-mimetic compound and oncolytic virus therapies synergize in driving CD8+ T-cell responses toward tumors through distinct activities. Smac-mimetic compound treatment with LCL161 reinvigorates exhausted CD8+ T cells within immunosuppressed tumors by targeting tumor-associated macrophages for M1-like polarization. Oncolytic virus treatment with vesicular stomatitis virus (VSVΔM51) promotes CD8+ T-cell accumulation within tumors and CD8+ T-cell activation within the tumor-draining lymph node. When combined, LCL161 and VSVΔM51 therapy engenders CD8+ T-cell-mediated tumor control in several aggressive mouse models of cancer. Smac-mimetic compound and oncolytic virus therapies are both in clinical development and their combination therapy represents a promising approach for promoting anticancer T-cell immunity.

Date: 2017
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DOI: 10.1038/s41467-017-00324-x

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