NG-348: a novel oncolytic virus designed to mediate anti-tumour activity via the potent and selective polyclonal activation of tumor-infiltrating T-cells
Brian R. Champion, Matthieu Besneux, Nalini Marino, Darren Plumb, Prithvi Kodialbail, Sam Illingworth, Rochelle Lear & Alice C.N. Brown
PsiOxus Therapeutics Ltd, 154B Brook Drive, Milton Park, Abingdon, Oxfordshire, OX14 4SD, UK
NG-348 is a transgene-modified variant of enadenotucirev, a chimeric oncolytic group B adenovirus with potent and selective anti-tumor activity against epithelial cancer cells. Enadenotucirev has been administered intravenously to over 90 cancer patients in studies that have shown delivery to tumors. NG-348 encodes two immunomodulatory proteins: human CD80 and a membrane-anchored single chain variable fragment of a mouse anti-human CD3ε monoclonal antibody. Together these membrane proteins provide both T-cell receptor (signal 1) and CD28 costimulatory (signal 2) activation signals required to effectively activate tumor-infiltrating T-cells independent of their antigen specificity. 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.
We have shown that NG-348 infected tumor cells potently stimulate activation marker expression (CD25, CD69), intracellular and secreted cytokines (IL-2, TNF, IFN), induction of T-cell mediated tumor cell death and activation of human T-cells in vivo, using a human tumor xenograft model system in immunodeficient mice reconstituted with human PBMCs. Transgene expression is controlled by the endogenous virus major late promoter which restricts protein production to cells permissive to virus infection (i.e. tumor cells). Treatment of non-tumor cells (e.g. fibroblasts, T-cells, PBMCs) with NG-348 did not lead to transgene expression or activation of T-cells in co-cultures.
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.