Hi Doc:
Thank you very much for your response.
I cannot comment upon your analysis wrt the hold but your speculation seems reasonable to me.
The issue that concerns me is the abstract's categorisation of M+ and M- broken down into associated molecular groups. The abstract is rather recent(February 26, 2018 publication date) and it focuses upon molecular groups. The graphic is pretty clear IMO wrt to M+. It does not indicate that M+ is predominantly pro-neural but rather suggests that M+ is ALL pro-neural in contra-distinction to M- which is PREDOMINANTLY made up of MES, classical and neural. This in itself causes some confusion because if M- is PREDOMINANTLY composed of these groups(not 100%) where does the remainder go? M+? If so, molecular groups other than pro-neural should be insignificant according to the graphic. Is the graphic wrong or is it misleading in some way? As an aside, neural is considered insignificant and is largely ignored in other studies as an important molecular grouping.
The question is: what molecular groups precisely compose M+/M- and what are their proportions? For example, is pro-neural 80% of M+ with classical and MES 20%? This is not addressed in the literature I have reviewed. It is possible that I missed something.
WRT to M-, I have to believe that a significant proportion is composed of MES. Much of the literature that I have reviewed suggests that between 25% to 45%+ of all ndGBM is MES(not broken down into methylated/un-methylated). MES is characterised as the most aggressive of the molecular groupings and this would follow the signature of MES/M- because there is no methylation and accordingly effecting of the cellular repair mechanism as would be the case for MES methylated which would inhibit it thus slowing down MES's aggressiveness in line with historical SOC OS medians for M+. No contradiction here. In fact, the combination of the immunogenic and methylated pathways would bode extremely well for MES/M+ as DC VAX L would be particularly effective and likely result in remarkable longevity, pursuing two pathways. However, I would suggest that MES/M+ is relatively a small molecular sub-grouping.
WRT to MES/M-, I would suggest that it makes up a significant proportion of the total M- group. I would also suggest that Drs. Liau and Prins' prior findings wrt to MES covered ALL of MES not just MES/M+. They did not break down MES into M+/M- in their studies. In fact, they concluded that particular efficacy wrt MES employing the vaccine was due to MES' immunogenic signature with significantly lesser micro-tumour environment immunosuppression(Treg down regulation) allowing more time for multiplied T-cell infiltration. There was no mention of methylation effect. In fact, according to the cited abstract, MES signature does not appear to involve mgmt methylation. Characteristics include NF-1 transcriptional errors and p 53 mutations. There is no mention of methylation.
As I have stated previously, M- OS 36 survival percentage is low at 14.3%. This may be due to the finding that about 50% of all ndGBM involves EGFr over-expression characteristic of Classical. You will recall that CLDX focussed upon this molecular sub-group(with HLA1/HLA2 immune system signatures). Assuming that Classical and MES are evenly split, the much less relative effect of the vaccine on this group could well mask remarkable survival of the equally large MES group.
The upshot of all of this suggests that the vaccine is quite effective for at least 50% of all ndGBM--M+ which might compose significant pro-neural(if the abstract is correct and not misleading)and a smattering of other molecular groups that exhibit mgmt methylation plus MES/M-. I don't see any significant overlap between M+ and MES but rather see these groups as distinctive and additive. There may be some lesser effect upon other molecular groups such as classical/EGFr which may not even be SS. Anyway, Dr. Ashkan's view is particularly noteworthy that as a clinician, he believes the vaccine should be made available to ALL patients as the vaccine works, to a greater or lesser extent, across the ndGBM landscape. It should also be noted that ndGBM tumours are not 100% one molecular group or another. There is great heterogeneity and accordingly, availability and use of the vaccine should be a function of patient/physician decision rather than imposed by regulatory fiat. Thus, if reg approvals are forthcoming, I believe they will be broad rather than limited and at least in line with Novocure.
BTW, I have long addressed the foregoing issues with other oncologists as well as with Dr. Boynton(who has never responded despite repeated follow-up; ditto with Innes and Dr. Rago) without clear response. Most did not address the foregoing and gave rather general responses. I must admit that all that I have talked/corresponded with are positive about DC VAX L potential and are anxiously awaiting results. The hire of Dr. Duffy is absolutely huge IMO. This confirms that big P is watching. This confirms the potential of DC VAX L. Dr. Duffy is extremely well versed in this space due to his academic credentials-he even has an MBA--and experience. He is willing to bet his career and reputation on NWBO. This is just a huge endorsement and a signal of great things to come.
Seems pretty obvious to me and I have been pretty much a skeptic in the past. JMHO. GLTA!
