I have no science background so a lot of what you ask is way over my head. I sent an email to Imugene asking some of these questions. The lovely Nick Ede has replied...
1) I'm wondering if there is any preclinical evidence that has demonstrated a significant benefit from intravenous administration of CF33 either as a single agent or in combination with an anti-PDL1 in every murine model tested? In cases where there may have been benefit, the clinical trial either administered the OV/combination immediately after transfection into the murine model or did not have a single-agent PDL1 arm.
As part of our preclinical package prepared for the FDA Investigational New Drug application (IND), we presented data to support the safety and efficacy of CF33 constructs by the IV route of administration. 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. 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. This is reported in O’Leary etal., https://doi.org/10.1186/s12967-018-1483-x
2) It has been speculated by a commentator that Intratumoral administration of anti-cancer agents for metastatic cancers is not and has never been an effective method of administration. In metastases, cancer has spread around the body and in most cases the cancer sites are not accessible by a needle. In the most recent announcement Imugene only accepted patients that had cancers close to the skin, and it was those specific cancer locations they were examining. Need I say that cancers in early stages that are close to the skin are removed surgically, so who exactly is your target market?
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.
3) Oncolytic viral therapy has always struggled to penetrate the tumor microenvironment, survive the immune system, and display significant efficacy in the clinic, which is why it's worth just $23-84M globally. Can you give a guide on the size of the market?
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.
Thank you
@Mason14 for sparking lots of debate. It has only strengthened my belief in what Imugene are doing.
