Expression of DAI by an oncolytic vaccinia virus boosts the immunogenicity of the virus and enhances antitumor immunity

Abstract

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.

Armed oncolytic viruses: A kick-start for anti-tumor immunity

“…VV-TRIF showed improved antitumor efficacy in colon and renal tumor models compared to VV-GM-CSF (Pexa-Vec). Similar results were obtained using intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI) as an vectorized immune modulator [103]. These studies show that the antitumor immune response can be switched from Th2 to Th1 by manipulating intracellular pathogen receptor signaling pathways in tumor cells.…”

oHSV2 Can Target Murine Colon Carcinoma by Altering the Immune Status of the Tumor Microenvironment and Inducing Antitumor Immunity

“…Consistent with previous works, our established rechallenge and bilateral tumor-bearing models showed that oHSV2 caused a systemic long-term antitumor immune response while exerting a direct antitumor effect. 23 This tumor-specific immune response effectively inhibited both secondary identical tumorigenesis and the growth of distant nontreated tumors.…”

Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model

“…Oncolytic viruses have been tested in preclinical studies and in numerous clinical trials against various tumor types, have a tolerable safety profile, and show varying degrees of efficacy. 8,[10][11][12][31][32][33][34][35][36][37][38][39][40] Their advantages include lysis of infected tumor cells, release of tumor antigens in an immunogenic milieu, and viral infection of adjacent tumor cells. In addition, Figure 5.…”