Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rβ2 or IL-18Rα

Abstract

The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in tumor cells and can transfer and amplify therapeutic genes. Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities. IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral administration of oncolytic Ad co-expressing IL-12 and IL-18, RdB/IL-12/IL-18. Intratumoral administration of RdB/IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine melanoma model. The ratio of T-helper type 1/2 cytokine as well as the levels of IL-12, IL-18, interferon-γ and granulocyte–macrophage colony-stimulating factor was markedly elevated in RdB/IL-12/IL-18-treated tumors. Mice injected with RdB/IL-12/IL-18 also showed enhanced cytotoxicity of tumor-specific immune cells. Consistent with these results, immense necrosis and infiltration of NK cells, as well as CD4+ and CD8+ T cells, were observed in RdB/IL-12/IL-18-treated tumor tissues. Importantly, tumors treated with RdB/IL-12/IL-18 showed an elevated number of T cells expressing IL-12Rβ2 or IL-18Rα. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-18 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.

Oncolytic adenovirus coexpressing interleukin-12 and shVEGF restores antitumor immune function and enhances antitumor efficacy

“…Cancer cells infected with RdB/IL12/shVEGF showed significantly higher IL-12 expression than those infected with RdB/IL12 (Figure 1B), implying that an additional expression of shVEGF in the E3 region of Ad may increase the expression of IL-12. This is in good agreement with our previous reports where insertion of additional transgene in the E1 or E3 region of Ad genome either attenuate or enhance expression of the transgene in the other region [9, 10, 12]. Furthermore, RdB/IL12/shVEGF-treated cancer cells exhibited the lowest VEGF expression among all treatment groups (Figure 1C), indicating that higher IL-12 expression in combination with co-expression of shVEGF can downregulate VEGF expression more effectively than control oncolytic Ads expressing single or no therapeutic genes (RdB, RdB/IL12, or RdB/shVEGF).…”

T-cell Subsets in Peripheral Blood and Tumors of Patients Treated With Oncolytic Adenoviruses

“…The immunological environment could also A c c e p t e d m a n u s c r i p t have an effect on the efficacy of chemotherapy 27,28 . Different chemotherapeutics as well as oncolytic viruses affect the differentiation 29 , activation 18,20 and migration 30 of lymphocytes to tumors.…”

Oncolytic adenovirus coexpressing interleukin-12 and decorin overcomes Treg-mediated immunosuppression inducing potent antitumor effects in a weakly immunogenic tumor model

“…Unicellular splenocytes were prepared as previously described [19]. Prepared splenocytes (1.5 × 10 6 ) were co-cultured with irradiated 4T1 (1.5 × 10 5 cells; 5 Gy) for 2 days in the presence of recombinant mouse IL-2 (100 units/mL, R&D Systems).…”