Hi there
@GreysaintnickYou ask a very good question. It's one I have given some thought to previously.
Mice are very small animals. My understanding is that even at 1 x 10
9 (one billion PFU), the toxicity/adverse reactions in preclinical studies were not catastrophic. This is why Yuman was so excited about the enormous therapeutic window for CF33, and why the company seems pretty confident that they can go to 3 x 10
9 in humans. Proportionate to the mass of a mouse (we are at least 2,500 - 3,000 times larger), one billion PFU for a mouse would be more like 2.5 - 3 x 10
12 (2.5 - 3 Trillion PFU).
Note: the science of comparing drug dosages between species is a bit more complicated than that, because it involves comparative surface areas as well. You can try reading this interesting "Simple Practice Guide" if you want to hurt your brain:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804402/However, the "Simple" guide is really aimed at chemical compound drugs, which are metabolised and excreted. Vaxinia is not a drug in that sense - it is actually an introduced viral infection.
The CF33 Vaxinia virus was derived from multiple strains of Orthpoxvirus, a family of pox viruses which includes Cowpox, Vaccinia - and Smallpox. Cowpox was used for the very first Smallpox vaccinations starting way way back with Edward Jenner in 1798. So we have 225 years of experience in investigating pox viruses as a therapeutic agent in humans. It all gets a bit complicated though, because back in 1798 they could not accurately determine between pox virus strains. Only in 1939 was it discovered that the Smallpox vaccine in use at the time was not actually Cowpox! At a certain point they zeroed in on Vaccinia strains for Smallpox vaccination - and the rest - including Smallpox - is history (barring the abominable military idiots who have developed weaponised versions Smallpox and stored them away).
The Wikipedia article on Vaccinia is an easy read and really really interesting:
https://en.wikipedia.org/wiki/Vaccinia#HistoryI have done some other reading which tells me that the Wikipedia version is about right. Of Vaccinia it says:
"
Vaccinia virus is closely related to the virus that causescowpox; historically the two were often considered to be one and the same.[8]The precise origin of vaccinia virus is unknown due to the lack of record-keeping, as the virus was repeatedly cultivated andpassagedin research laboratories for many decades.[9]The most common notion is that vaccinia virus, cowpox virus, andvariolavirus (the causative agent of smallpox) were all derived from a common ancestral virus. There is also speculation that vaccinia virus was originally isolated fromhorses,[8]and analysis of DNA from an early (1902) sample of smallpox vaccine showed that it was 99.7% similar to horsepox virus."
Either way - a lot is known by now about how Vaccinia and other Orthopox virus types act in the human body, and how the human body reacts to them. The reason they are still being cautious with dose escalation in the MAST trial is that CF33 Vaxinia is NOT identical to any previous strain of "Vaccinia" or any previous virus in the Orthopoxvirus family (of which Vaccinia is a member).
Why not? Well - here is the process they used to develop CF-33:
"Nine strains of orthopoxvirus were used to create CF33 by co-infecting CV-1 cells and fostering chimerization. These were cowpox virus strain Brighton, raccoonpox virus strain Herman, rabbitpox virus strain Utrecht, vaccinia virus strains Western Reserve, IHD, Elstree, Connaught Laboratories, Lederle-Chorioallantoic, and AS, all purchased from ATCC and grown and titrated in CV-1 cells. Following the co-infection, 100 individual plaques were chosen and then subjected to a total of three rounds of plaque purification in CV-1 cells to obtain 100 clonally purified chimeric orthopoxviruses. High-throughput screening was used to compare the cytotoxic efficacy of these chimeric clones and the parental strains against the NCI-60 panel. CF33 was selected as the chimeric isolate which demonstrated superior cell killing in the NCI-60 panel when compared to all parental viruses and other plaque-purified isolates. "
Source:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026443/So - quite a scary sounding soup, right there, but it was a way of accelerating viral evolution - and then applying "unnatural selection" to the resulting herd. Instead of "survival of the fittest" - Yuman and team selected for "survival of the deadliest" - but only those deadly against cancer, and harmless against normal cells. And CF33 was the best of the best at that task.
I don't think the FDA was worried about starting the Zombie Apocalypse, but you can understand why they made IMU start at what Prof Fong called "Teeny Tiny dosages," and imposed a DLT gap of a few weeks between dose escalation events to be sure they caught any Doe Limiting Toxicity "adverse events."
At this point though, all the signs indicate that CF33's action on healthy cells, and on the human metabolism and immune system, and on cancer cells too thank goodness, is pretty much what they expected. Mild flu like symptoms, basically, while killing cancer cells and alerting the immune system to those that survive.
So I think they are most likely to see a flattening off in the effectiveness against cancer, before they see anything like severe reactions to Vaxinia.
I mean - at a certain point - the body will be so flooded with Vaxinia that any cancer cell that's going to be infected (before the immune system clears the Vaxinia), will indeed have been infected - and a higher dose of Vaxinia will not produce a meaningful increase in benefit. The dose level where that therapeutic benefit peaks will be the OBD. It would seem very unlikely indeed that the MAST trial will do any serious harm to a patient.
Compare that to the current actual Standard Of Care for Bile Duct Cancer - used extensively to treat BDC patients. The combo of Chemo plus a MAB immunotherapy drug (Durvalumab) literally
kills 3.6% of patients. See my post:
https://hotcopper.com.au/threads/imu-product-line-cf33.7741190/page-10?post_id=71884095"Holy kill you to cure you, Batman!!???.... "
So by comparison, and indeed by any measure so far -
CF33/Vaxinia isincredibly safe- and I think we can be pretty confident of that continuing.
Cheers
Dave
(20min delay)