I would say they are similar in principle. Use the maturational cocktail to optimally mature the dendritic cell pre-cursors that come from the PBMC's from the leukapheresis.
Though this is more time critical with Direct so that you derive 'adolescent' dendritic cells, that have both migratory capacity to lymph nodes and also antigen presenting abilities.
And it's incorrect to say that Direct 'uses none' of the tumor antigens. It uses all of them, at least theoretically.
It's just that with L the antigen presentation is in vitro and with Direct it is in in vivo. But the fundamental principle is the same.
There is no guarantee that they will have equivalent efficacy.
Direct may elicit a lower response rate than L, or it might actually be better. Who knows?
Direct manufacturing is simpler due to only having the one autologous component and not two, and that is probably why Direct is more amenable to closed system automated manufacture. Which will likely make it cheaper to produce, and possibly a cheaper therapy.
I think everything is more time critical with Direct, because the intention will always be to administer it asap after manufacture.
There is a detailed paper floating around somewhere that came out of the Direct P1, which went into quite a lot of detail about how they had learned the time critical partial maturation, which they had previously referred to as Method B (for better).
And I remember thinking that they were in danger of giving their secrets away in that paper, because it was so detailed.
But I've lost the bookmark somehow.
Don't know if anyone knows the one I'm talking about, and can perhaps put up the link.
It's somewhat moot as to what extent an approved L could be used off-label. I don't see why it couldn't be used in other cancers wherever there is a tumor resection, if the responsible physician believes its use is justified. Though that might be pushing off-label discretion a bit far.
For sure, I think it could be used off-label for any type of resectioned brain tumor, not just GBM.
Yes the first Direct P3 would take a while, and you would come straight up against a single-arm versus a randomised study dilemma.
Randomised would bring up all the ethical issues of denying a control a potentially life-saving treatment, and injecting a tumor with a placebo??
But with a single arm, how do you get a control comparison?
So trial design would be critical to ensure that you get a speedy outcome that gives you data that warrants approval. Would Direct be granted the same smooth passage as the Car-T single arm studies? I very much doubt it.
I loathe tumor response rate as a surrogate for OS, but if they wanted AA through interim analysis, that is probably what they would think of using.
Think you're being too negative about this. If L is approved everything else should follow, if a level playing field exists.
The resistance and obstacles would come from the status quo, that would recognise Direct as a big challenge to the established order in cancer treatment.
Just opinion.
