Senti:
I would congratulate you on the excellent article find and the analysis it has presented.
In my view, and I am admittedly not a professional, this article is extremely important and highly suggestive of corroboration of what I have thought and explained in my previous post. The key takeaway is that both MES and classical molecular sub types are IDHwt and M+. While the article does not explain the classification of pro-neural as the only M+ subtype as presented by the Feb. 2018 article, it is more recent and hence more authoritative. Furthermore, proneural subtype is characterized as IDHmt. I do not understand the progression from a lower grade “aggressive” astrocytoma to proneural since proneural is not considered an aggressive subtype. The article focuses upon methylated rather than non-methylated and so the next question I would have is whether M- contains IDHwt MES and classical? And/or whether M- contains these classifications as IDHmt?
And if so, relative effectiveness wrt SOC ad DC VAX.
This article explains the importance of both methylation and IDH status and accordingly, it is obvious as to why NWBO attached importance to this which may have caused some delay. Completely understandable given its importance.
In addition, the article reinforces the classification of three molecular subtypes to which my post alluded: MES comprising about 35% of the nGBM population, classical about 50% and proneural about 15%. What this means is that DCVAX L appears to be effective across a relatively broad cross-section and that the tail is not only long but robust. This is confirmatory of what LG emphasized to me in one of our discussions where I suggested that the vaccine was a “one trick MES pony” and accordingly if any approval were to be issued, it might be limited to the MES signature. LG said that was not the case and that the tail was robust and long in his opinion. Hence, the vaccine seems to be very effective for M+ MES IDHwt and at least somewhat effective for M+ classical IDHwt. M+ in the trial is about 40% of the overall ITT( 38 un-categorized) and about 44% of the categorized N= 293. So two out of three major classifications are covered. This is huge IMHO.
Insofar as the M- classifications go, these might include proneural which would be a relatively small percentage and MES plus classical. Proneural would be IDHmt and I expect that even though un-methylated, MES and classical might be characterized as IDHwt, although I don’t know this as a fact. These could be IDHmt if there is such a thing. What we do know from three year old JTM blinded data is that M- has a delta of 7 months from surgery. Accordingly, the vaccine is effective to some degree for most of the ITT population. This is in accord with the statements of Drs. LL and KA. And especially since 90% of the ITT population was exposed to early/late vaccination.
The article does make a rather curious statement at least to my thinking. It states that MES IDHwt which has a high intra-tumoral heterogeneity would be more susceptible to CI therapy. This is rather contra-indicative of the findings of LL and RP where MES had a higher incidence of residual TILs and a lesser immunosuppressive tumor micro-environment which would suggest that in such cases, DCVAX L could act as a mono-therapy.
The other important statement is that the article mentions diversity in heterogeneity wrt inter-tumoral cancers underscoring the importance of personal therapies as opposed to off the shelf.
Finally, and very importantly, the article acknowledges the tendency of molecular types to morph into MES where DC VAX is especially effective particularly in the case of recurrent GBM. Hence the inclusion of rGBM in the secondary endpoint category where there is presently no really effective rGBM therapy. Quite an important inclusion in the SAP. And good odds for achieving this endpoint, otherwise NWBO may not have included it.
In conclusion, from my analysis of this article, it is extremely telling and IMHO strongly suggests significant trial success.
The market may not have found this article of significant consequence and it may have escaped notice by many busy oncologists at the present time—they will catch up—but to those of us who follow such developments more closely, this article is a major big deal. I am sure our resident and wise physician Iwasadiver might well agree with this characterization.
Many thanks for this gem, Senti, and you have done the board a great service. Just excellent DD, good for you and good for us all! Indeed, come Tuesday, I will buy some more :))
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