OncoSec Medical Inc (ONCSQ)

[hschlauch]

Thanks for your post Danger.

Perhaps one reason to stay "under the radar" could be to gain a headstart relative to competitors

The addition of encoded flt3 ligand should significantly improve antigen presentation and priming by expanding the number of dendritic cells in the presence of tumor antigens. Given what we know about Tregs and their constitutive expression of CTLA-4 as well as their shared binding to CD86 and CD80 on dendritic cells, it seems obvious (to me at least) that flt3 ligand will cancel out adaptive immune suppression caused by CTLA-4. In theory, this could potentially negate the need for anti-CTLA-4 administration. Cancer antigen presentation gets hijacked intratumorally and in tumor draining lymph nodes, so I think administration of encoded flt3 ligand with IL-12 could be maximized if done in both sites. If my hypothesis is correct, and it appears that the combination is working very well across multiple solid tumor models, then this would certainly explain why the preclinical work is completely under wraps right now, i.e. to have a competitive advantage. You could be right.

The data I've seen relative to flt3 ligand is quite intriguing and it could explain the responses we've seen with intratumoral administration of encoded IL-12. It now seems very apparent that IL-12 contributes to the activation and expansion of NK cells - an innate response - thus promoting more cross communication with dendritic cells through flt3 ligand expression (originating with NK cells). Again, this leads to improved priming through downstream expansion of antigen presenting cells.

I'm also beginning to see interest growing in NK cells and their upregulation of surface PD-1 upon activation. If IL-12 is activating and expanding these NK cells, and interferon gamma is contributing to the upregulation of PD-1 on their surface, then it would help to explain the responses we're seeing with an anti-PD-1 combination. It may also explain why some patients with very few Teff cells at baseline experience responses to anti-PD-1 monotherapy.

You certainly could be right about the patient population in the PISCES trial having a spectrum of lesion sizes. Those would be interesting data points. Regarding Treg elimination, I also don't think that is the best approach. Absolute Treg numbers aren't predictive of responses. I think we're going to discover that it's the ratio of intratumoral dendritic cells to Tregs (found intratumorally and in/around draining lymph nodes) during the priming phase that are most predictive of adaptive responses. And that is where IL-12 and flt3 ligand come in.