Expression of DAI by an oncolytic vaccinia virus boosts the immunogenicity of the virus and enhances antitumor immunity.
In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI) to boost the innate immune system and to activate adaptive immune cells in the tumor. We showed that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways. Treatment with DAI-armed VV resulted in significant reduction in the size of syngeneic melanoma tumors in mice. When the mice were rechallenged with the same tumor, DAI-VV-treated mice completely rejected growth of the new tumor, which indicates immunity established against the tumor. We also showed enhanced control of growth of human melanoma tumors and elevated levels of human T-cells in DAI-VV-treated mice humanized with human peripheral blood mononuclear cells. We conclude that expression of DAI by an oncolytic VV is a promising way to amplify the vaccine potency of an oncolytic vaccinia virus to trigger the innate-and eventually the long-lasting adaptive immunity against cancer.
Laboratory of ImmunoViroTherapy, Centre for Drug Research (CDR), Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , Helsinki, Finland.
Mari
M
Hirvinen
Laboratory of ImmunoViroTherapy, Centre for Drug Research (CDR), Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , Helsinki, Finland.
Cristian
C
Capasso
Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki , Helsinki, Finland.
Kilian
K
Guse
Laboratory of ImmunoViroTherapy, Centre for Drug Research (CDR), Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , Helsinki, Finland.
Mariangela
M
Garofalo
Department of Movement Sciences and Wellness (DiSMEB), University of Naples Parthenope and CEINGE-Biotecnologie Avanzate , Naples, Italy.
Andrea
A
Vitale
Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki , Helsinki, Finland.
Marko
M
Ahonen
Laboratory of ImmunoViroTherapy, Centre for Drug Research (CDR), Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland; Oncos Therapeutics Ltd., Helsinki, Finland.
Lukasz
L
Kuryk
Institute of Biotechnology, University of Helsinki , Helsinki, Finland.
Markus
M
Vähä-Koskela
Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland; TILT Biotherapeutics, Ltd., Helsinki, Finland; Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
Akseli
A
Hemminki
Finnish Institute of Occupational Health , Helsinki, Finland.
Vittorio
V
Fortino
Finnish Institute of Occupational Health , Helsinki, Finland.
Dario
D
Greco
Laboratory of ImmunoViroTherapy, Centre for Drug Research (CDR), Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , Helsinki, Finland.
Vincenzo
V
Cerullo