NG-347 is armed with three transgenes (Figure 1.):
- Secreted interferon alpha: IFNα
- Secreted Macrophage Inflammatory Protein: MIP1α
- Membrane bound CD80
IFNα is a potent type I interferon that is regulated by the Stimulator of Interferon Genes (STING) signalling pathway and acts to stimulate macrophage, NK cell and dendritic cell activation and drive immune effector cell-mediated cytotoxicity in solid tumors (Figure 2.). IFNα is also one of the primary initial drivers of innate anti-viral responses. However, the T-SIGn platform virus has been shown to be insensitive to IFNα. For this reason, high intra-tumoral concentrations of IFNα can be achieved with NG-347 without affecting the replication of the viral vector. By directly driving high intra-tumoral concentrations of IFNα, NG-347 bypasses the STING pathway to activate immune-mediated anti-tumoral cytotoxicity directly.
STING agonists have been suggested as possible anti-cancer therapeutics and several are in development. However, STING agonists have two key disadvantages:
- The STING pathway is frequently defective in tumor cells, with a range of mutations possible, both upstream and downstream of STING itself, thus providing potential mechanisms for resistance and escape (Figure 3.).
- Systemic activation of the STING pathway would be excessively toxic and so STING agonists require intra-tumoral administration.
NG-347 is delivered systemically and produces the IFNα directly within the tumor, bypassing the STING pathway and its associated signalling defects while minimizing systemic exposure and toxicity (Figure 4.).
The activity of IFNα is supported by two additional transgenes within NG-347:
- Secreted MIP1α (also known as CCL3) is a chemokine that drives inflammatory cell recruitment and the release of other pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α.
- Membrane bound CD80 which will act as a co-stimulatory ligand to enhance T-cell activation.
NG-347 is a preclinical compound with a planned clinical start in 2019.