Abstract 4561: Oncolytic vaccinia virus encoding IL-7 and IL-12 systemically sensitizes tumors to anti-PD-1 antibody in a syngeneic mouse model
Authors: Nakao Shinsuke , Yamashita Midori , Tasaki Mamoru , Kawase Tatsuya , Nakatake Motomu , Kurosaki Hajime , Mori Masamichi , Takeuchi Masahiro , Nakamura Takafumi 
Published: September 2020

Abstract
Immune checkpoint blockade targeting PD-1, PD-L1 and CTLA-4 have demonstrated remarkable clinical responses in patients with advanced cancers; however, a durable benefit is obtained in only a subset of patients. To overcome this therapeutic limitation, a number of immunotherapies and their combinations have been investigated. Among these, in situ vaccination using tumor-selective oncolytic viruses has proved an attractive approach. Viruses not only directly kill cancer cells through their replication, but also activate antitumor immunity triggered by the release of tumor antigens from killed cells. We have explored this approach using tumor-selective oncolytic vaccinia viruses (VVs) carrying immunomodulatory genes. We previously demonstrated that intratumoral treatment with a VV carrying human IL-7 and murine IL-12 genes (hIL-7/mIL-12-VV) enhanced immune responses in treated tumors and induced complete tumor regression in syngeneic mouse models (AACR-NCI-EORTC 2019). Here, using a bilaterally tumor-bearing mouse model, we examined whether unilateral virus injection affected untreated distant tumors. All tumors that had been directly injected with hIL-7/mIL-12-VV completely regressed. At the same time, untreated tumors in three of six mice also disappeared. We further confirmed significant increases in tumor-infiltrating lymphocytes in both treated and untreated tumors after treatment with hIL-7/mIL-12-VV. Unlike the treated tumors, the untreated distant tumors showed no detectable viral DNA by qPCR. PD-L1 expression was also upregulated in this model following treatment with hIL-7/mIL-12-VV in both treated and untreated tumors. This led us to examine the effects of combining this virotherapy with anti-PD-1 antibody. While monotherapies with anti-PD-1 antibody did not show significant antitumor efficacy, hIL-7/mIL-12-VV prior to this agent elicited improved antitumor activity in the virus-untreated distant tumors, suggesting that hIL-7/mIL-12-VV systemically sensitized tumors to anti-PD-1 antibody. Evidence that intratumoral immune status was changed following hIL-7/mIL-12-VV was found in the upregulation of various immune pathways analyzed using the Nanostring Pancancer Immune Profiling panel, and the increased clonality of T-cell repertoire in tumors. These results support the clinical development of VV carrying IL-7 and IL-12 as both monotherapy and as a combination partner with anti-PD-1 antibody for patients with advanced tumors.
Citation Format: Shinsuke Nakao, Midori Yamashita, Mamoru Tasaki, Tatsuya Kawase, Motomu Nakatake, Hajime Kurosaki, Masamichi Mori, Masahiro Takeuchi, Takafumi Nakamura. Oncolytic vaccinia virus encoding IL-7 and IL-12 systemically sensitizes tumors to anti-PD-1 antibody in a syngeneic mouse model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4561.