Given that Red's thesis is the one that I understand best, I've tried to relate the results to the ratio of efficacy, T "killer" to T regulatory cells, CTL:Treg.
Using that model but not believing that one can translate preclinical stuff to the START trial (I've made it very clear that, thus far, we've seen no indication that the p = 0.12 had anything to do with blp25-specific responses), I've tried to flesh out a model, CTL vs. Treg.
Fact is, the Merck trial was poorly designed. Don't know if it could have been done better at the time. I can understand wanting to get into as many centers as possible to accrue a broad representation of the world's patients in as little time as possible, and I probably would have recommended inclusion of both sCRT and cCRT. And I don't know anything about the ethics of giving cyclophosphamide instead of saline to placebo recips.
But that cut (sCRT vs. cCRT) is also something that a good regulatory agency would have recommended, if Merck had omitted it. Contrary to popular opinion, meetings between sponsors and FDA, to plan a trial? They are generally of a collaborative spirit, and existing data pointed to the need for the cut's inclusion.
(Hiro and Steve... I haven't been near a lab since the mid-90s. I should be considered as a well-informed layman.)
I would love for Red to be correct (tip of iceberg, benefit of cancer patients) and thus I've modeled that sCRT-Treg > cCRT-Treg, and that immunization of sCRT patients leads to profound tolerance. The effects of focal radiation on the induction of profound regional tolerance are well known. But getting from a subcutaneous injection site to the lung is, thus far, all hand-waving.
Out of here for a couple of days.
Best, all!
Rick |
