NorthWest Biotherapeutics Inc (NWBO)

[Umibe5690]

Thanks Doc

I have not found any article or other evidence that methylation status changes upon recurrence. However, upon recurrence, these cancers are very aggressive with survival times averaging between 6 and 9 months. There is shift to MES and indeed it appears that the recurrent tumor is largely composed of MES. However, it seems curious to me that while the MES is highly aggressive in the recurrent case and perhaps even more so than in nGBM, a methylation status would seem contra-indicative due to interference with the cellular repair mechanism thus increasing survival rather than aggressively attenuating it. We know that in M+ groupings, as illustrated by the JTM data, survival is significantly longer than in cases of M- Accordingly, it may be that M+ MES is much more aggressive than the blended/blinded 21.7 month SOC median survival, but that the much greater and thus less aggressive classical molecular subtype in the M- significantly counterbalances the much more aggressive MES component. Further, the significant improvement of the blended/blinded survival when adding in DC VAX into the mix has more to do with dramatically increasing MES survival, but less so for classical. That would make sense to me. Further, in this particular trial, we do know that crossovers originally were resectable but at this point, do not know for sure that the recurrent tumor is non resectable. It probably is resectable because these recurrent tumors usually grow back into the originally resected bed. The application of DCVAX in rGBM also serves to address migratory cells which the MES recurrence/morphing appears to stimulate thus inhibiting extra-local growth.

In any event, it would appear that good results can be achieved in 2 out of 3 major molecular groups without resort to in combination CIs for both nGBM and rGBM.

Thanks again for your comments.