Abstract 3714: Stealth liposomes encapsulating plasmid DNA of telomerase specific oncolytic adenovirus
Authors: Yoshihiko Kakiuchi
Journal: Cancer Research (2018)

Abstract Background: Oncolytic virotherapy has the potential to become the next breakthrough in cancer therapy. We previously established a telomerase-specific oncolytic adenovirus (Telomelysin), which is controlled to replicate and induce oncolytic cell death selectively in tumor cells, and its safety for humans was proven in the phase I clinical trial performed in the USA. While oncolytic adenoviruses have promising antitumor effects, the application is basically limited to local administration because of non-specific trapping in the liver and immune elimination after systemic delivery. Liposomes are among the most common nanoparticles used as drug carriers, and liposome-encapsulated therapeutic agents enhance the efficacy by increasing their stability in the bloodstream. We investigated the potential of liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus as an oncolytic adenoviral agent suitable for systemic delivery. Methods: TelomeScan, a modified Telomelysin expressing the green fluorescence protein (GFP), was used in this study. Cytotoxic effects of TelomeScan plasmid DNA-lipid complexes (Lipo-pTS) and control GFP plasmid DNA-lipid complexes (Lipo-pGFP) against HCT116 colon carcinoma cells were evaluated in vitro and in vivo. Coxsackie and adenovirus receptor (CAR) blocking assay using anti-CAR antibodies and neutralizing assay using adenovirus type 5-specific antibodies (AdNAbs) were performed to assess the CAR-independency of Lipo-pTS in infectivity and the influence of AdNAbs on Lipo-pTS cytotoxicity, respectively. Immunogenecity of Lipo-pTS was evaluated by assessing the productivity of AdNAbs after systemic administration in immune-competent BALB/c mice. Results: Lipo-pTS, which has a diameter of 40-50 nm, showed potent antitumor effects on HCT116 cells compared to Lipo-pGFP in vitro and in vivo, by producing actual viable adenoviruses after Lipo-pTS treatment, leading to tumor-specific oncolytic cell death. Infectivity of Lipo-pTS was not affected by pretreatment of anti-CAR antibodies, while infectivity of TelomeScan was reduced to less than half by anti-CAR antibodies, which suggested that tumor selectivity of Lipo-pTS was independent of CAR expression. Importantly, Lipo-pTS reduced production of AdNAbs significantly after intravenous administration into BALB/c mice compared to TelomeScan, and even in the presence of AdNAbs, Lipo-pTS maintained strong cytotoxicity in contrast to TelomeScan whose cytotoxicity was almost nullified by AdNAbs. These findings proved that Lipo-pTS possesses a stealth effect on the immune system in vivo environment, meaning that systemic delivery of Lipo-pTS may be possible. Conclusion: Lipo-pTS has the potential to become an oncolytic adenoviral agent suitable for systemic delivery with the characteristics of CAR-independent antitumor activity and a stealth effect on the immune system. Citation Format: Yoshihiko Kakiuchi. Stealth liposomes encapsulating plasmid DNA of telomerase specific oncolytic adenovirus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3714.