Modifying the cancer-immune set point using vaccinia virus expressing re-designed interleukin-2

Zuqiang Liu, Yan Ge, Haiyan Wang, Congrong Ma, Mathilde Feist, Songguang Ju, Z. Sheng Guo and David L. Bartlett ()
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Zuqiang Liu: University of Pittsburgh School of Medicine
Yan Ge: University of Pittsburgh School of Medicine
Haiyan Wang: University of Pittsburgh School of Medicine
Congrong Ma: University of Pittsburgh School of Medicine
Mathilde Feist: University of Pittsburgh School of Medicine
Songguang Ju: Soochow University
Z. Sheng Guo: University of Pittsburgh School of Medicine
David L. Bartlett: University of Pittsburgh School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract The complex immune tumour microenvironment requires an equally complex immunotherapy approach, especially when the cancer-immune set point is non-inflamed. Oncolytic viruses expressing immune activating cytokines might optimally modify the immune microenvironment and improve the antitumour effects. In this study, we have explored a variety of IL-2 constructs expressed by a tumour-selective oncolytic vaccinia virus, designed to maintain IL-2 in the tumour microenvironment to reduce systemic toxicity. An IL-2 construct combining a glycosylphosphatidylinositol (GPI) anchor with a rigid peptide linker leads to functional IL-2 expression on the tumour cell surface and in the tumour microenvironment. This virus construct effectively modifies the cancer-immune set point and treats a variety of murine tumour models with no toxic side effects. In combination with PD-1/PD-L1 blockade this virus cures most of the mice with a high tumour burden. This combination represents a treatment for cancers which are to date unresponsive to immunotherapy.

Date: 2018
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DOI: 10.1038/s41467-018-06954-z

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