OncoSec Medical Inc (ONCSQ)

[dangerM]

Sunday reading...

... I really wonder if I should share this article from 2015 directly with Oncosec. It's the first I have read which directly links IL-12, (p)Tregs and an IDO-pathway inhibitor.

Regulatory Rebound in IL-12-Treated Tumors Is Driven by Uncommitted Peripheral Regulatory T Cells
www.jimmunol.org/content/jimmunol/195/3/1293.full.pdf?with-ds=yes

I strongly believe the challenge stated by the authors (Tregs impairing IL-12 therapy) does not or does only to a much, much smaller degree apply to the small, continuous dosing of IL-12 that is achieved with plasmid-based pIL-12 treatment. Else we would have seen problems much, much earlier. It could be a hint to closely watch the more effective P2A-linked next-gen plasmids (which might produce higher IL-12 levels in the tumor) and their effect for Treg generation, but it's irrelevant now.

Actually, much more positively, I believe it gives the scientific rationale for the dosing schedule (at day 1/5/8 in Pisces, discarding the larger spaced day 1/8/15-schedule in treatment arm B from OMS-100). I believe this helps to overwhelm with Teff before Tregs can fully expand (with conventional IL-12 the pTregs-effect would show on day 7 according to the article).

Probably everybody is sleeping now because of the dry topic. Sorry. The most interesting part of the article was this:

"Expansion of pTreg was strongly inhibited in the presence of 1-MT, an inhibitor of both paralogues of IDO, IDO-1, and IDO-2 (Fig. 5A). Specific targeting of IDO-1 and IDO-2 with L-1MT and D-1MT, respectively (39), revealed that both enzymes contributed to the pTreg expansion. D-1MT had a slight but significant advantage over L-1MT ... In contrast, blockade of PD-L1 or TGF-b did not result in significant suppression of pTreg proliferation (Fig. 5B, 5C), although a slight trend toward reduced pTreg expansion was observed in the presence of anti–TGF-b Ab (Fig. 5C). These data are consistent with our previous finding that the IFN-g–IDO axis was a major contributor to the posttreatment Treg rebound in IL-12–treated tumors (13, 17)."

At the current time Oncosec probably has no interest in further collaborations (so I only shared the article with Newlink). However, after Pisces is a success, IMHO such a combo would be one of the most interesting trials to follow.



Have a nice Sunday everyone!

dM