NorthWest Biotherapeutics Inc (NWBO)

[longfellow95]

Hi Senti

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-015-0536-8

This article (which I have previously posted) 'Advances in the Treatment of Newly Diagnosed Glioblastoma' has some useful breakdowns of sub-types and indications of their prognostic significance.

On MGMT methylation:-

In addition to establishing the standard of care, the EORTC-NCIC trial retrospectively demonstrated that patients with MGMT promoter methylation have an improved prognosis compared to those patients with unmethylated promoter regions [17]. In both the EORTC-NCIC trial and another single-institution retrospective study, newly diagnosed GB patients with MGMT promoter methylation treated with upfront radiotherapy alone had improved survival outcomes, suggesting that MGMT promoter methylation may be prognostic regardless of upfront treatment; however, patients with MGMT promoter methylation treated with temozolomide had the best overall survival outcomes in the EORTC-NCIC trial [9, 18].

And as is now more accepted (at least by Dr Cobbs), TMZ just does not work with unmethylated tumors.



IDH mutations are 'nearly absent' in primary GBMs. Maybe 0-5%.
Whereas IDH mutations are seen in the majority of secondary GBMs.
IDH mutation leads to an approximate doubling of OS. (Kat is probably benefitting from having a secondary GBM which is likely to be IDH mutant, as well as receiving L of course.)

Also:-

The majority of IDH1 mutant high-grade gliomas also have MGMT promoter methylation, and IDH1 mutation is a stronger prognostic biomarker than MGMT promoter methylation [32, 33, 34, 35]. Combined analysis of IDH mutation and MGMT promoter methylation may improve prognostication over analysis of either biomarker alone, although the prognostic significance of MGMT promoter methylation may be more significant in IDH1 wild-type tumors [35, 36].

And on G-CIMP and mesenchymal:-

Nearly all the G-CIMP tumors have IDH1 mutations and a proneural pattern of gene expression, and have an improved prognosis [39]. This distinct subgroup of GBs, with a G-CIMP phenotype and IDH1 mutation, represent only 5–10 % of GBs in total. By contrast, GBs with a mesenchymal gene expression pattern have inferior survival outcomes with an average OS of 12 months or less and make up a much larger proportion, approximately
30 %, of GB patients.

The bottom line for all this, is that, imo and I'm sure you will agree, DCVaxL is likely to show advantage in all subgroups, but particularly for those that traditionally do worst. i.e. mesenchymal, unmethylated, IDH wild type.
We know the cohort is being stratified by methylation status. Don't know about IDH status, and I doubt that TCGA subclass was prospectively established (though this may be possible by retrospectively testing remaining tumor sample.)

We know that other 'enhancements' were announced in Aug '14, but the only one they told us about was white bloodcell count.

One hopes that this will all become apparent in the final analysis to the satisfaction of the FDA. It's another reason why NWBO need, in discussion wlth the FDA, to ensure that the analysis takes in to account these key variables in the light of recent research, and do so before unblinding.