Abstract LB-206: The synergistic antitumor effect of the combination of three transgenes delivered by the oncolytic vaccinia virus, KLS-3020

Abstract

Oncolytic viruses that selectively kill cancer cells are a promising platform for fighting cancer. Vaccinia virus is a good candidate for the oncolytic virus because it has several advantages such as a proven safety profile, broad host tropism, and larger capacity to harbor multiple transgenes. We removed three viral genes (C11R, K3L, and J2R) from wild-type vaccinia virus to obtain a backbone virus, which is selectively replicating in cancer cells. Then, we inserted three transgenes (PH20, sPD1-Fc, and IL-12) into the backbone virus to boost up the antitumor efficacy, which is the final construct named KLS-3020. We investigated the biological activity of transgenes with the intratumorally injected backbone viruses containing each single transgene in syngeneic mouse tumor models. At first, the backbone virus expressing PH20, an enzyme which can degrade the tumor extracellular matrix, showed enhanced virus spread compared to the empty backbone virus in melanoma or colon cancer. Likewise, locally expressed sPD1-Fc, which is a fusion protein of the extracellular domain of PD-1 and Fc region of an immunoglobulin, resulted in the increase of INF-γ+CD8+ and INF-γ+CD4+ T cells in melanoma, indicating T cell re-activation in the tumor site. Lastly, delivered IL-12 in lung cancer mouse model resulted in a significant increase of T-bet+CD4+ T cell populations, indicating the oriented differentiation of helper T cell into T helper 1 (Th1) cells. We compared the efficacy of oncolytic vaccinia virus containing a combination of three transgenes (KLS-3020) with ones expressing each single gene in syngeneic mouse tumor models and observed that KLS-3020 could control tumor growth more effectively than every backbone virus having a single gene. Finally, we evaluated the anti-tumor efficacy of KLS-3020 in various types of mouse tumor models. Intratumorally injected KLS-3020 could suppress the growth of various tumors without significant body weight loss. Our results suggest that enhanced virus spread combined with the immune-stimulatory activity of KLS-3020 synergistically increase antitumor efficacy in a broad range of tumor types. Citation Format: Jaeil Shin, Soon-Oh Hong, Minjung Kim, Heonsik Choi, Sujeong Kim. The synergistic antitumor effect of the combination of three transgenes delivered by the oncolytic vaccinia virus, KLS-3020 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-206.