NG-348 is the first T-SIGn virus and is designed to drive T-cell immune responses locally within the tumor microenvironment. It is a transgene-modified variant of enadenotucirev encoding two immunomodulatory MiTe proteins in its genome. The two MiTe proteins encoded within NG-348 are:
- A membrane anchored full-length human CD80
- A membrane anchored antibody fragment specific for the T-cell receptor CD3 protein
When expressed together on the surface of NG-348 infected tumor cells, these two membrane proteins provide both the T-cell receptor (signal 1) and costimulatory (signal 2) activation signals required to polyclonally activate tumor-infiltrating T-cells in an antigen independent manner (Figure 1.).
NG-348 therefore enhance the potency of the virus by driving local T-cell immune responses selectively within the tumor microenvironment. In essence, this approach is the mirror image of CAR-T therapies, which modify the patient’s T-cells ex vivo, whereas NG-348 modifies tumor cells in situ. The key advantages of NG-348 over the CAR-T approach are:
- An off the shelf product: no need for autologous cell processing
- Antigen agnostic: no need to select for any given tumor specific antigen(s)
- Directed towards solid tumors: enadenotucirev effectively infects tumor cells within primary and metastatic solid tumors.
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. NG-348 infected tumor cells potently activate both CD4 and CD8 human T-cells, both in vitro and in a human tumor xenograft model. By contrast, non-tumor cells exposed to NG-348 do not express the MiTe proteins or activate T-cells. Thus, following delivery to tumor tissues of patients, NG-348 oncolytic virus should selectively replicate and express it’s payload of T-cell activating ligands and stimulate 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.