Doc Logic:
You have put your finger on an extremely note-worthy point wrt M- and mesenchymal(MES). According to the February 26, 2018 abstract entitled "Development of Targeted Agents in Immunological Therapies:
A Personal Approach" referred to as per the chart associating molecular sub-groups with M+ and M- in the iHUB message board intro(just scroll down and you will come to it), M- is predominantly composed of Classical, Neural(de minimis) and MES( my recollection is that only about 5% of MES is M+) and M+ is associated with the much slower progressing pro-neural molecular sub-group which primarily affects younger patients. The JTM and SNO updates showed remarkable blended results for both M+ and M-.
Prior studies conducted at UCLA by Drs. Liau and Prins showed that the DC vaccine worked particularly well for MES--because it was more immunogenic, however, it had little to no effect upon pro-neural. This appears contrary to the JTM blended findings with respect to M+ if the abstract's classification of pro-neural being associated with M+ is accurate. In the DC VAX L trial, the M+ population was approximately 44% of the categorised overall patient population(N=293). Pro neural is characterised by IDH 1 mutation as well as PDGFr mutations. On the other hand, MES in the M- group is very aggressive with a very abbreviated survival after SOC is applied. MES is characterised by NF 1 transcriptions and p 53 mutations. MES has been estimated to comprise anywhere between 25%~48% of all ndGBM(and appears to mutate into MES upon recurrence) which is a significantly large molecular population. That combined with M+(apparently at least predominantly pro-neural according to the quoted abstract chart) covers at least 50% of the ndGBM population where DC VAX L appears to be particularly efficacious. In addition, Classical/M- is characterised by EGFr amplification/mutations which comprise perhaps 50% of all ndGBM as stated in this abstract. Apparently, even in this significant molecular sub-group, DC VAX L appears to be at least somewhat efficacious.
The update at SNO indicated that OS36 survival improved to 14.3% for the M- group. However, MES may have significantly superior survival outcomes masked by the lesser efficacy of classical resulting in an overall blended 14.3% OS 36 survival percentage. The long tail at OS 60 may be composed predominantly of M+ however, MES may show remarkable survival percentages at the OS 36 and 48 milestones with a drop-off thereafter due to its highly aggressive signature. Overall, considering the foregoing, the vaccine appears to be working to a greater or lesser extent over all groups(neural is insignificant) and Dr. Ashkan's statement, as a clinician who experiences these types of patients on a daily basis(as does Dr. Liau), that the vaccine should be available to all patients has great import. Accordingly, if reg approvals issue assuming positive results as the blended results appear to point to, such approvals will likely be broad and leave the decision as to whether to invoke DC VAX L as an adjuvant therapy between physician and patient rather than by regulatory fiat. This may also include--perhaps off-label--using DC VAX L as a mono therapy in M-cases such as MES as you have wisely pointed out due to relative ineffectiveness of current SOC.
The abstract has also mentioned, matter of factly, that PFS may not be an appropriate surrogate for OS in immunological trials and that pseudo-progression has been a confounding issue. As I have suggested previously, it may be that even where there may be earlier than heretofore expected eventing that as the DC VAX L therapy gains strength over time, the progression itself is slowed thus contributing to longer OS and better QOL.
Doc, I would appreciate your comments on the foregoing especially with respect to the seeming contradiction between UCLA earlier results and those suggested in JTM/SNO. All in all, it looks very promising. Thanks for your prescient insights. JMHO.
