Next Generation Oncos Oncolytic Adenovirus With Novel Anti-Cancer Double-Transgenes Shows Synergistic Anticancer Effect In Melanoma Mouse Model

Oncolytic virotherapy is a promising anti-cancer strategy utilizing genetically engineered viruses to preferentially infect, replicate in and lyse cancer cells. To date, Talimogene laherparepvec is the only FDA approved oncolytic virus (OV), however, many other types of OVs are showing promising results in clinical studies. One example is ONCOS-102, an adenovirus serotype 5/3 chimera expressing GM-CSF as a transgene, which recently reported 33% ORR in advanced anti-PD1 refractory melanoma. Genetically engineered OVs can be armed with different co-stimulatory molecules in order to boost the anti-tumour immune responses. Building on the ONCOS-102 backbone, we have engineered two next generation ONCOS viruses, ONCOS-210 and ONCOS-212, expressing novel double transgenes designed to inhibit tumor growth and metabolism. Here, we describe the characterization and pre-clinical in vitro and in vivo testing of ONCOS-210 and ONCOS-212. The oncolytic properties of ONCOS-210 and ONCOS-212 were confirmed in 4 melanoma cell lines in vitro, demonstrating robust cell lysis and induction of immunogenic cell death. Anti-cancer effects of the viruses were also assessed in i) immunodeficient xenograft and ii) humanized xenograft mouse models to further understand the anti-cancer and immune stimulatory potency of the constructs. Intra-tumoral ONCOS-210 and ONCOS-212 resulted in robust anti-tumor activity in both immune-deficient and immune-competent mice. The double transgenes were shown to act synergistically in vivo, in line with the design hypotheses and proposed mode of action to induce cell lysis and prevent tumor growth. Moreover, the vectors were able to increase tumor infiltration of various immune subsets including CD4+, CD8+, CD8+ expressing PD1+ or CD8+ expressing Granzyme B T cells and reduction of regulatory T-cells and MDSC in the tumour microenvironment, suggesting an ability to prime immune-suppressive tumors to better respond to immunotherapy. These encouraging preclinical findings will be further investigated to elucidate the mode of action and perform toxicological studies to bring ONCOS-210 and ONCOS-212 towards clinical testing. Citation Format: Lukasz Kuryk, Anne-Sophie Moller. Next generation Oncos oncolytic adenovirus with novel anti-cancer double-transgenes shows synergistic anticancer effect in melanoma 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 4562.