Hi friend TB
Well - just a brief answer to this now, because I'm juggling a few tasks and also because I really don't know.
What I think though - without any specific evidence - is that your own thoughts on this seem reasonable to me.
In strictly scientific terms the company and the FDA have to treat the three products - Vaxinia, Checkvacc and OnCARlytics - as three different products, because that's what they are, but it is true that they are all variants of CF33. So we have three separate dose escalation trials, and a fourth if we count the Vaxinia/Pembro trial as distinct, because that's the safe thing to do. The OBD for each drug may well turn out to be different.
However the three versions of the CF33 virus do all have three things in common:
- they only infect cancer cells;
- they have the capacity to destroy cancer cells,
- by infecting the cancer cells they also identify those cells as targets for the immune system.
The only differences are that Checkvacc also delivers a Checkpoint Inhibitor, and OnCARlytics forces the cancer cells to express a CD19 marker which then makes them targets for CD19 directed therapies.
Yuman's view on this is that the genetic manipulation required for Checkvacc to deliver a Checkpoint Inhibitor, and for OnCARlytics to force CD19 expression, possibly weakens the innate direct cancer killing/lysis properties of the virus. In Checkvacc it's a trade off, to see whether the possible weakening of the direct cancer lysis ability is offset by the presence of the Checkpoint Inhibitor, which should minimise the cancer's ability to turn off the immune system T-cells. In OnCARlytics the hope is that a small weakening of direct cancer lysis is more than offset by the fact that it marks the cancer cells for destruction by a combination CAR-T drug (or any CD19 targeting therapy, such as the Blincyto Bispecific T-cell Engager drug they are using in the trial).
So yeah - I'm sure they are comparing can data from all three trials to see how rapidly and comprehensively the virus replicates in the tumour, both with IT and IV. They will also be comparing safety/tolerability data from all three trials. And for sure they will be looking really really closely at the range of immune system/immunological cell that were shown in Figures 4 and 5 of the presentation to the ASCO Gastrointestinal Cancers Symposium back in January:
https://static1.squarespace.com/sta.../1705619461250/749 ASCO-GI MAST-Final (1).pdf
Although the detail will no doubt fluctuate between the three variations of CF33, I think they are already seeing strong commonality - in safety/tolerability and virus replication. Hopefully also in the immune system markers.
If efficacy is also good - then that commonality of data between the three studies will be a powerful argument for the viability and success of the overall CF33 "core" product.
It will be fascinating to see if Yuman is correct in predicting that Vaxinia - the least genetically "manipulated" virus - turns out to have the strongest innate cancer lysis ability of the three.
I'm going well beyond my scientific knowledge here - but I think you are right when you say that common responses in specific tumour types will be considered significant. eg. If OnCARlytics turns out to be particularly effective in Bile Duct cancer - will that be considered as reinforcing the Biliary Cancer results in the MAST trial? I don't think it can be considered as "proof" - because how could they tell whether the effect was the CF33 virus, or the CD19 targeting combo drug? But I do think it would be considered as "indicative" - if they see common efficacy across the Vaxinia and OnCARlytics trials in specific cancer types. Also - if the Checkvacc trial does end up showing good effect against TNBC, and they also see good effect against TNBC with Vaxinia and/or OnCARlytics.
I hope that answer your question, mate. Bear in mind that I am not trained in this - though I have done a lot of reading over the last few years, lol.
Easter is good so far, here in the beautiful Northern Rivers. I fixed my bike and went for a long ride along the Clarence...
Cheers
Dave
PS Planning to make this my last post for a while!
See ya again when the Conference paper drops.....
(20min delay)