Hi Abeta:
The majority are unmethylated(M-). The March, 2017 study calculated M+ to be 39.6% of the ITT or 331 patients. However, 38 early patients in the trial were not classified as to M+ or M-. Hence the KNOWN classified populations of M+ and M- were 131 and 162 patients respectively or a total of 293 patient. Of the KNOWN population, M+ is 44.7% of 293. Having methylation promoter means you are in the M+ group. What it means is that methylation interferes with MGMT over-expression and cellular repair. That results in longer survival. M+ is characterised by pro-neural and that sub-group which is less than 20% of all stage IV glios is known to have longer survival. You can note that in the publication where control in this M+ group is 21.7 months and the blended mOS is 34.7 months.
M- is unmethylated, i.e., without methylation promoter, and thus sub-groups in this classification are more aggressive. MES is predominantly unmethylated. It can constitute up to 50% of all stage IV glios. LL and RP reported from their own clinical findings that the vaccine appeared to be most efficacious in the MES sub-group. The reason, they believe, is because this sub-group is very heterogenous and presents many antigen targets which plays into DC VAX L's strength. Secondly, MES is immunogenic which means that the micro-tumour environment is less immunosuppressive allowing more time for T-cell, etc. infiltration and T-reg down-regulation. The vaccine also appears to be efficacious for CLASS, also in the M- group, although less so as compared to MES. As you may recall, CLDX's peptide vaccine was focused upon CLASS with EGFRviii mutation in a patient population having HLA1/2 immune systems.
From the publication you will note that the vaccine appears to be quite remarkably efficacious in the M-group. Control mOS is 12.7 months and blended is 19.8 months. The delta to BLENDED is 7 months. For TX, it would be over 8 months. Remarkable.
For the M+ group which is composed of pro-neural, I am in the dark as to why the vaccine appears to be so effective. It may have something to do with G-Cimp status. However, LL and RP found that the vaccine was not efficacious for pro-neural as a whole, so I cannot reconcile the two results. There is something missing and that is why it is an anomaly, at least to me. I think it is safe to say that the long and thick tail will be made up of M+ predominantly with some MES thrown in. I don't think that cross-over will significantly affect the trial, but even if it does, it is not necessarily a bad thing. It could very well mean that the vaccine is efficacious for rGBM and the trial WAS NOT DESIGNED FOR THAT. It may be that upon recurrence, the tumour(s) mutate to MES where the vaccine is more effective. And this might occur in spite of the fact that a de minimis number of patients had resections post recurrence! Obviously, all this can be analysed upon unblinding. Stay tuned.
Hope this helps.
AI
