Although I'm sure Davy will have a lot more to add as our most well-researched poster, I'll try to avail him of some of his summer Sunday as much as possible. I'm 'stuck' indoors in a rainy Florence anyway.
1. Yes, there has been preclinical evidence suggesting CF33 works in GI cancers (found here) and also peritoneal cancers (found here and here). As you will note in these studies, IT is where CF33 really performed. Similarly, the Bile Duct patient who achieved CR was IT. So I would say that patient selection was done considering these stellar results achieved pre-clinically. Does this mean that CF33 performs better in GI cancers than others? I don't think so. I believe IMU know CF33 worked well in these cancers preclinically; they know these cancers are immunologically cold and do not respond to checkpoint inhibitors and chemo. Therefore an early win in these cancers could mean an early win for CF33. IMU will not have to provide OS or PFS to a large extent if they can prove surrogate benefits sooner, i.e., tumour shrinkage t-cell activation, etc. Final point: a total of 36 patients have been trialled if I remember correctly, most of which were dosed at "tiny doses", so I believe it's still far too early to tell where CF33 will ultimately prove most effective.
2. This is a great question. Logic would suggest that it would speed things up considerably. Rather than "interrogating" the dosage for safety and efficacy and getting an FDA nod to proceed, once OBD is determined, it would mean they'd just be able to administer that dosage to patients across all sites. In my correspondence with management, the MAST trial has been designed to be able to move to Phase II seamlessly. That said, it seems like the expansion cohorts may be the avenue IMU exercises to achieve expediency. Remember that the expansion cohort for Bile Duct, for example, will only start once OBD is determined, likely in this current cohort or the next, based on Leslie's comments.
3a. Yes, it has been documented, but relatively early days, it seems. With the rise of immunotherapies and their effectiveness, a lot more work has been done to identify biomarkers and surrogate endpoints that have a positive relationship with tumour killing/shrinkage. Surrogate endpoints like increased CD4+ and CD8+ in circulation and the tumour microenvironment suggest a causal effect on tumours. Very loosely, if T-Cells increase due to therapy, therapy is directly helping to kill the tumour. If this increase in T-cell circulation also correlates to tumour stability or shrinkage, as the poster shows, then its suggestive therapy is beneficial. Especially in cancers known to be immunologically cold (the body's immune system doesn't recognise the tumours). See here for a paper that goes into this in more detail.
3b. It's quite telling when you consider the gold standard for determining a therapy's effectiveness is still overall survival (patients lived longer) and progression-free survival (how long the therapy stopped the cancer from getting worse). I'm not suggesting that patients living longer and not progressing isn't a positive thing. However, it's questionable that they are still the best means to determine a therapy's effectiveness. A therapy can increase progression-free survival and lead to no increase in overall survival and still be approved. How does that make sense? Not to mention, they do not at all account for patient-centric outcomes, like well-being, long-term negative effects, etc. Anyway, that was a bit of a rant; all of this is to say IMU seems to be working very hard to provide surrogate data that unequivocally show real benefit from its therapies. They are doing this on many fronts. Tumour shrinkage is one, and they have hNIS to help with this (MAST study secondary outcomes is objective response rate (ORR), which is tumour shrinkage shown by radio-imaging); tracking tumour microenvironment (T-Cells) is another. I also believe they have been successful in achieving this, considering the Bile Duct expansion cohort getting fast-track designation based on CR and the durability of this response (400+ days now?).
On another note, with regards to your comments on pseudoprogression, it's unlikely that we will ever know whether patients who progressed early in the MAST study were actually due to genuine cancer progression or pseudoprogression. It's also unlikely they'd be allowed back into the study if it was determined to have been pseudo.
Final comments: I genuinely believe we are still well and truly in early days territory for CF33. Based on cohorts and also on the therapeutic window CF33 has. The trial design has set things up extremely well for early approval if ORRs keep coming in positively, especially for cancers which fall in the unmet need category.
(20min delay)