Abstract 5098: NG-348: a novel oncolytic virus designed to mediate anti-tumour activity via the potent and selective polyclonal activation of tumor-infiltrating T-cells

Abstract

Abstract NG-348 is a transgene-modified variant of enadenotucirev, a chimeric oncolytic group B adenovirus with potent and selective anti-tumor activity against a range of epithelial cancer cells. Enadenotucirev has a blood stability profile that enables systemic dosing and has been administered intravenously to over 90 cancer patients. These studies have demonstrated that IV dosed enadenotucirev is delivered to tumors and subsequent virus activity is associated with CD8+ T-cell infiltration in tumor cell nests, consistent with immune stimulation within the tumor. NG-348 encodes two immunomodulatory proteins in its genome: full-length human CD80, and a membrane anchored single chain variable fragment of the mouse anti-human CD3ϵ monoclonal antibody OKT3. Together these membrane proteins provide both T-cell receptor (signal 1) and costimulatory (signal 2) activation signals required to polyclonally activate tumor-infiltrating T-cells. When expressed on the surface of NG-348 infected tumor cells the transgenes therefore enhance the potency of the virus by driving local T-cell immune responses selectively in the tumor microenvironment. The expression of both transgenes encoded in the NG-348 virus is controlled by the endogenous virus major late promoter. This restricts expression of the proteins to the surface of cells permissive to virus infection (i.e. tumor cells) and prevents off-target expression in the cells from healthy tissues. Using co-cultures of human T-cells with human tumor cell lines, we have shown that NG-348 infected tumor cells potently activate both CD4 and CD8 T-cells. This was demonstrated by analysis of activation marker expression (CD25, CD69), intracellular and secreted cytokines (IL-2, TNF, IFNγ) and induction of T-cell mediated tumor cell death by apoptosis (prior to oncolytic death by the virus). Treatment of different human non-tumor cells (e.g. fibroblasts, T-cells, PBMCs) with NG-348 did not lead to transgene protein expression or activation of T-cells in co-cultures. NG-348 has also been shown to activate human T-cells in vivo, using a human tumor xenograft model system in immunodeficient mice reconstituted with human PBMCs. Collectively these data indicate that following delivery to tumor tissues of patients, NG-348 oncolytic virus can selectively replicate and express it’s payload of T-cell activating ligands. NG-348 should therefore stimulate potent antigen-independent, polyclonal activation of T-cells already present in the tumor, as well as those recruited into the tumor in response to the virus infection, to drive effective anti-tumor immunity. NG-348 is currently in preclinical development with a first phase I study planned to initiate in Q4 2017. Citation Format: Brian R. Champion, Matthieu Besneux, Nalini Marino, Darren Plumb, Prithvi Kodialbail, Sam Illingworth, Rochelle Lear, Alice C. Brown. NG-348: a novel oncolytic virus designed to mediate anti-tumour activity via the potent and selective polyclonal activation of tumor-infiltrating T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5098. doi:10.1158/1538-7445.AM2017-5098