Abstract 3551: Oncolytic adenovirus serotype 35-mediated activation of NK cells leads to efficient anti-tumor effects

Abstract

Abstract Oncolytic adenoviruses (OAds) are getting much attention as cancer immunotherapy agents. Almost all OAds are based on human adenovirus serotype 5 (Ad5) (OAd5). However, OAd5 has several drawbacks which possibly attenuate the anti-tumor effects of OAd5. More than 80% of adults have neutralizing antibodies against Ad5. The expression of coxsackievirus-adenovirus receptor (CAR), which is the primary infection receptor of Ad5, often declines on malignant tumor cells. Previously, we have developed a novel OAd fully composed of human adenovirus serotype 35 (Ad35) (OAd35) (Ono et al., Mol.Ther.Oncolytics, 2021). Only 20% or fewer adults have neutralizing antibodies against Ad35. Ad35 recognizes CD46, which is highly expressed on malignant tumor cells, as an infection receptor. OAd35 showed efficient tumor cell lysis activities in many types of tumor cells; however, the mechanism of anti-tumor effects of OAd35 remains to be fully evaluated. In this study, we examined the mechanism of anti-tumor effects of OAd35. Although OAd35 showed efficient tumor growth suppression at levels comparable to OAd5 following intratumoral administration in nude mice bearing H1299 human lung cancer xenografts, the genome copy numbers of OAd35 in the tumor were about 500-folds lower than those of OAd5 at 18 days after administration and were almost background levels. These data suggest that other mechanisms different from infection of tumor cells with OAd35 were involved in the anti-tumor effects of OAd35. Since previous studies reported that Ad35 efficiently activated innate immunity in natural killer (NK) cells, we examined whether OAd35-mediated activation of NK cells contributed to the anti-tumor effects of OAd35. Intratumoral administration of OAd35 resulted in efficient infiltration and activation of NK cells in H1299 tumors. In contrast, OAd5 did not apparently induce the infiltration and activation of NK cells in the tumors. OAd35-mediated activation and infiltration of NK cells were also found in B16 tumor-bearing immunocompetent mice. Next, in order to examine the roles of NK cells in the anti-tumor effects of OAd35, NK cells were depleted by intravenous injection of anti-GM1 antibody in nude mice, followed by intratumoral administration of OAd35. The depletion of NK cells significantly attenuated the anti-tumor effects of OAd35 on H1299 tumors. Furthermore, pretreatment with anti-GM1 antibody significantly increased the genome copy numbers of OAd35 in the tumor, suggesting that activated NK cells removed the OAd35-infected tumor cells. This study demonstrated that OAd35 significantly activated NK cells following intratumoral administration and that activated NK cells efficiently removed the tumor cells, leading to efficient tumor growth suppression. Citation Format: Ryosuke Ono, Kosuke Takayama, Fuminori Sakurai, Hiroyuki Mizuguchi. Oncolytic adenovirus serotype 35-mediated activation of NK cells leads to efficient anti-tumor effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3551.