While immune checkpoint inhibitors have markedly improved therapeutic outcomes for cancer patients, only a subset of patients exhibit a long-term durable response. A number of approaches have been trialed in preclinical and clinical studies to overcome this, including in situ vaccination using tumor-selective oncolytic viruses. Oncolytic vaccinia virus (VV), which is highly cytolytic across a wide range of tumor types, kills cancer cells and induces antitumor immune responses via DAMPs, PAMPs and tumor antigen release. To maximize the potential of oncolytic virus therapy, we examined methods to further upregulate a tumor’s inflammatory status based on the intratumoral IL-7 or IL-12 expression. IL-7 is crucial for T cell homeostasis and is known to increase tumor-reactive T cells. Meanwhile, IL-12 is known to activate both innate and adaptive immunity via IFN-γ produced by NK cells, cytotoxic T cells and CD4-positive T cells. We engineered and administered VVs carrying human IL-7 (hIL-7-VV) and murine IL-12 (mIL-12-VV) and evaluated antitumor responses in immunocompetent mice with poorly immunogenic Lewis lung carcinoma (LLC) tumors. Monotherapy with hIL-7-VV or mIL-12-VV induced complete tumor regression (CR) in 0 or 1 of 7 mice, respectively, whereas combination treatment with hIL-7-VV and mIL-12-VV induced CR in 4 of 7 mice with no body weight loss. Intratumoral injection of hIL-7-VV in combination with mIL-12-VV significantly increased tumor-infiltrating lymphocytes and induced murine IFN-γ production. Mice that had previously achieved CR following treatment with a VV carrying both human IL-7 and murine IL-12 (hIL-7/mIL-12-VV) rejected rechallenged tumors, suggesting that hIL-7/mIL-12-VV induced the establishment of antitumor immune memory. Next, to assess the effect of oncolytic activity and immune activation potential against human tumors, we engineered a VV carrying human IL-7 and human IL-12 genes (hIL-7/hIL-12-VV) and evaluated its effect in humanized mice bearing human cancer cells. Intratumoral administration of hIL-7/hIL-12-VV altered the immune status of tumors and induced tumor regression, consistent with the activity of hIL-7/mIL-12-VV observed in immunocompetent mouse models. Therefore, oncolytic VV-induced intratumoral IL-7 and IL-12 expression enhanced the immune response in the tumor microenvironment and improved antitumor efficacy. These results support the clinical development of VV carrying IL-7 and IL-12 for patients with non-inflamed cold tumors.

Citation Format: Shinsuke Nakao, Yukinori Arai, Mamoru Tasaki, Midori Yamashita, Nobuaki Amino, Ryuji Murakami, Tatsuya Kawase, Motomu Nakatake, Hajime Kurosaki, Masamichi Mori, Masahiro Takeuchi, Takafumi Nakamura. Effect of oncolytic vaccinia virus-induced IL-7 and IL-12 expression on tumor immune microenvironment in poorly immunogenic murine cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B019. doi:10.1158/1535-7163.TARG-19-B019