Wheres can this UPI article be found that everyone keeps referring to??
The Drudge report times out.
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Announcement from ERM has made my day. :)
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@mrdingo, it's great that your post has got so many likes. This means that everyone will take extra care when reading the response, I hope.
There are a few key things that you missed in your review of the CF33 IV-specific literature. I've included it below.
Let's take it from the top:
1. For example, in Chaurasiya etal., https://doi.org/10.1016/j.omtm.2021.12.002 , equivalent tumour inhibition was observed in a murine model of breast cancer for both IT and IV delivery. Importantly, the biological activity and function of the anti-PDL1 checkpoint inhibitor encoded transgene was also confirmed.
The IV efficacy that this study is quoting is specifically for the non-human xenograft tumor murine model. When we look specifically at the human tumor xenograft model from the same study, the preclinical states that only intratumoral injection was completed.
From a researchers perspective, if the OV/PDL1 hybrid has shown intravenous efficacy in an inferior murine model, then you would think that they would test it in a human derived xenograft - as this is the closest thing that resembles a response in humans. The researchers have not shown whether IV is an applicable method in human derived xenograft models, so it is incorrect to state that IV line administration has shown equal efficacy to IT. I suspect the IV administration showed no efficacy, which is why the results were not stated in this publication. This is of extreme importance as this study was used to reinforce the phase 1 clinical trial currently underway.
https://www.cell.com/molecular-therapy-family/methods/pdfExtended/S2329-0501(21)00188-1
2. Additionally Woo etal., https://doi.org/10.1016/j.jamcollsurg.2019.12.027 , presented some excellent data for pancreatic ductal adenocarcinoma (PDAC) models. CF33-hNIS-antiPDL1 killed PDAC cells in a dose-dependent manner, achieving >90% cell killing by day 8. Cells infected with CF33-hNIS-antiPDL1 also produced bioactive anti-PD-L1 antibody, which blocked PD-1/PD-L1 interaction. In vivo, a single IV dose of virus reduced tumour burden and prolonged survival of treated mice. Whilst it was observed that IP administration of CF33-hNIS-antiPDL1 was more effective than IV administration, systemic delivery still resulted in very effective tumour growth inhibition. Importantly the abscopal effect has been demonstrated where CF33 virus injected in a right flank tumour of pancreatic cancer, travels systemically through the mouse to a left flank tuour and inhibits the growth of both tumours.
To post this reassures me that you are not reading the literature that you quote. Here is the overall survival data from the in vivo work from this study. As you can see from the figure below, D0 IV and D2 IV line follows the line of PBS (a saline solution with no anti-cancer efficacy) almost exactly. There is a slight improvement from D2 administration, but it is still not significant and certainly not worthwhile clinically. In the D0 IV group, the overall survival is actually worse than a saline solution. What is also significant about this survival data is that it is a human derived xenograft - indicating limited to no efficacy in a murine xenograft model most related to humans from an IV line.
This information can be found on page 17/17.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8787938/pdf/nihms-1771143.pdf
3. This is reported in O’Leary etal., https://doi.org/10.1186/s12967-018-1483-x
This research paper includes research specifically targetted at intratumoral injections of the OV/PDL1 hybrid. Once again, no IV efficacy.
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1483-x
All of this research combined provides very clear indication that the combination of CF33 with PDL1 has not and does not show efficacy through IV administration. To say that it does is misleading and erroneous.
4. The commentator is partly correct that until now the IT delivery of oncolytic viruses has not been effective in treating metastatic disease. We believe CF33 will change this in a paradigm shift for oncolytic virus therapy. Our preclinical data suggests we will succeed due to the extreme potency of CF33 and its demonstrated abscopal tendencies. We look forward to releasing human data at the appropriate time. In relation to the question on only injecting tumour lesions that are accessible and close to the skin, this was a requirement of the FDA for our first in human studies. We do look forward to expanding the dosing soon to include patients with visceral and deep lesions. I’d like to highlight though an outstanding result published last week at the AACR meeting in the US. Please refer to the poster on our website, https://www.imugene.com/conference-presentations, that presented data showing that “surface” TNBC lesions we have been injecting quickly become necrotic, ie the tumour tissue is dying.
Well, it's either going to be CF33, the >100 other clinical trials, or none. All that clinical and commercial risk must be heavy on the shoulders.
It's widely accepted that IV therapy for metastatic cancer is far better than IT. I'd say that a molecule that can't even demonstrate efficacy from IV administration is going to change this. Think about it: the virus would have to travel from the tumor of origin via the blood stream - where it has shown no efficacy...
5. Oncolytic viruses have struggled to gain traction in the oncology market due to the early versions, such as Amgen’s T-Vec for melanoma, being too highly attenuated which leads to less than optimal response outcomes and hence poor market growth and penetration. As Professor Fong has discussed on numerous occasions, the FDA was overly cautious for the first versions onto the market and tested in humans. Hollywood does have influence! Prof Fong and others now are ready to change this with new generation oncolytic viruses that have been engineered to be far more specific for cancer cells only, and far more potent. The second half of the 2020’s may just be the coming of age for oncolytic virus therapies and hence a new market player. Prof Fong, CF33 and Imugene are leading the way. Additionally the impact that our onCARlytics platform could have on solid tumour treatment is simply huge and will follow on naturally from the data being generated in our MAST trial. The next 2-3 years are going to a very exciting time for Imugene, our patients and of course our shareholders where we can create a new market for OV therapy from the $400Bil solid tumour market.
This is hope and not backed by science. It is not 'a' player, it's literally placed in a sea of competitors- huge clinical and commercial risk. Prof Fong, CF33, and Imugene are at the back in the que, which is in fact about 400 clinical trials and 31 products behind (and that's only from Oct 2021).
The market is small because OV therapy is ineffective in humans. From their $90M placement, IMU intend on investing almost as much money to expand CF33 (AUD $19M) than the OV market is worth (AUD $32M).
It is my belief based on many hours of research that there are multiple clinical and commercial risks for CF33. Holders of this forum hold an overly positive outlook on the drug that is not corroberated by the scientific literature to date. I believe the limited IV efficacy will be confirmed in humans, which will have significant clinical and commercial impact on the drug leading to a downstream effect on company shareholders. Of course, I could be wrong, and I hope I am for all of the people who have tied up their hard-earned savings.
Last edited by Mason14: 27/04/23
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