Harnessing NG-348: Unleashing Tumor-Targeted Immunotherapy through Polyclonal T-cell Activation

NG-348 is a modified form of enadenotucirev, a chimeric adenovirus that targets various epithelial cancers with high efficacy. It has been administered intravenously to over ninety cancer patients, and it has been shown to reach tumors where it stimulates an immune response characterized by CD8+ T-cell infiltration. NG-348's genome includes two immunomodulatory proteins: full-length human CD80 and a modified version of the OKT3 monoclonal antibody, which together provide activation signals necessary for the polyclonal activation of T-cells within the tumor microenvironment.

The expression of these proteins is regulated by the virus's major late promoter, ensuring that they are only expressed on the surface of cells susceptible to viral infection, such as tumor cells, and not in healthy tissues. In vitro studies using human T-cells and tumor cell lines have demonstrated that NG-348-infected tumor cells can effectively activate both CD4 and CD8 T-cells, as evidenced by the expression of activation markers and the production of cytokines. Additionally, NG-348 has been shown to induce T-cell-mediated tumor cell death through apoptosis. Importantly, NG-348 does not induce T-cell activation in non-tumor cells such as fibroblasts or peripheral blood mononuclear cells (PBMCs), nor does it lead to transgene protein expression in these cells.

In vivo studies using a human tumor xenograft model in immunodeficient mice with human PBMCs have also shown that NG-348 can activate human T-cells. The data suggest that NG-348, once delivered to tumor tissues, can selectively replicate and express its payload of T-cell activating ligands, thereby stimulating a potent and antigen-independent polyclonal activation of T-cells in the tumor. This is expected to drive a robust anti-tumor immune response. NG-348 is currently in preclinical development, with plans for a phase I study to begin in the fourth quarter of 2017.

The abstract was presented at the American Association for Cancer Research Annual Meeting in April 2017, by Brian R. Champion, Matthieu Besneux, Nalini Marino, Darren Plumb, Prithvi Kodialbail, Sam Illingworth, Rochelle Lear, and Alice C. Brown, and is available in the Cancer Research journal supplement.