STAT1

Interferons are very potent activators of cell mediated, for example, T cell mediated immunity.

So TH1 cells with high levels of expressing transcription factor TBET, along with STAT1, will start producing interferon gamma.

Interferon gamma and that cascade of immune events will be responding normally just to intracellular pathogens like bacteria, and that will result in macrophage inflammation.

But The naive CD-positive T4 cell, in order to get to an active TH1 cell, TBET-producing, STAT1-producing, also would be then modulated by other cytokines.

Those would be typically interleukin-12 and 18.

Now, if that same naive CD-positive, CD4-positive T cell is is encountering high levels of interleukin or another modulatory cytokine.

And there we know that the virus has taken hold, it's formed the beachhead, and it's having a profound replicative effect that we ultimately recognize will then stimulate the immune system, and again, modify certain biological pathways.

Maybe if I can, just to, to finish up on that point, the line of clinical data and thinking that we're trying to pursue is, we noted from some of our RNA analyses that several of the biological pathways, one in particular in STAT1, has been implicated in platinum resensitization.

Tumor fibroblasts, the glutathione pathway can down-regulate, which enables the tumor to expel platinum.

We showed the ability to up-regulate STAT1 in a statistically different way, and we believe that the effector cells, whether those are against the virus backbone, some of the payload proteins, or of course, the tumor neoantigens, any of those, we believe, has the ability to have that reversal effect on the STAT1 pathway.

And as a consequence, what occurs is you get initial viral infection, the immune response, both the direct and the immune cell death, but you also through that set the tumor microenvironment up to be rechallenged by platinum.

And when rechallenging by platinum, and when the platinum isn't removed from the tumor, it does two things.

I haven't quite caught is, what is it about that resensitizes the tumor to platinum?

So that's a great question.