Ann: Imugene to present at 2024 Cholangiocarcinoma Conference, page-218

Some observations about the state of the CF33 nation. Just rambling thoughts, not investment grade advice.

Looking at the AACR presentation, the CRpatient tumor at baseline was 33.4mm x 25.9mm and assuming an out-of-plane widthof say 20mm gave a volume of roughly 9cm3. That gives a tumor cell count of about 9e8 cells. The pt was injected IT which allows a rough comparison of multiplicity of infection MOI with the mice studies. The pt was injected with 1e7 PFU so the MOI was roughly 0.01 or in other words the virus was outnumbered 90 to 1. This compares with the lowest MOI of 0.01 in mice. The point? When CF33 works it works very well and only needs a low dose to get going.

As an aside, the CR pt was injected midNov 2022 and the CR result was confirmed 120 days after injection, sometime in Mar2023. The result was informed in the announcement in Nov 2023, some 8 mths later. I wonder who knew this result during that time.

So why did it work in that pt and notothers? IMU provided a possible reason in their analysis of SPECT imaging where a close correlation between viral replication and tumor response was indicated. I’m sure that the scientists are working very hard to split the data to determine what was different about the TME in the CR pt. A further possible reason is provided in the analysis of T Cell diversity, also mentioned in the posters. So now we’ve shifted from obliterating all cancers to responders and non-responders. I guess the hope is to only allow pts with suitable T Cell diversity onto the bile cancer expansion.

Vaccinia has no known latency (likeherpes virus for example) and should start producing virions after about 6 hrs so42 days should be plenty of time to see an impact. If we accept pseudoprogression (as is a feature of TVec) and the CR pt as a good example, then 120 days should be more than enough to see a real tumor response. It’s not being impatient to expect results when they should be due, and they're overdue!

The R_R story is a cage rattler. Empathy aside, I can’t think of anything more valuable in an investment sense than inside info. OK N=1 but it seems that his bloods (ie liver damage) were heading south from the first injection. I wish him well and admire his spirit. I’m very cynical and will be looking closely at whether this is recorded as an SAE. R_R did mention that his tumor size hadn’t changed so I wonder if he goes down as an SD. Looking closely at the dates I’d say he’s not in the expansion cohort.

While I’m venting my fears, IMHO if nakedCF33 doesn’t perform, the rest is on very thin ice. The CD19 stuff is a great idea worth exploring but vaccinia has had eons to evolve immune escape systems both from proteins forming its capsid to early expression proteins and right through to its exocytosis stage. For example, it secretes proteins that inhibit IFNs, inhibit T Cell signaling and a host of other strategies to not arouse the immune system. There are also viral genes to avoid apoptosis. My point is that the CF33 strategy is swimming upstream if success depends on immune activation or checkpoint inhibitors rather than naked proliferation and lysis.

Fong’s use of directed evolution toscreen CF33 was a great idea and it stands on the shoulders of previous OVs. Others are following in those footsteps. My fear is that more genetic engineering is required to address the emerging issues of inadequate infection and/or inadequate virulence.

Best of luck to those holders braverthan me. I'll be back after the next CR or when the science points in the right direction.

I want to add a passing shout out to @slick who IMV was the only poster to urge caution during the great turning at 60c, and to @illuminati for reminding us about the lighter side of life and that laughter really is the best medicine. Oh, and also my fellow pseudoscientists.