Hi Doc:
Thank you very much for your response. I am sure you are quite right in your analysis and are obviously further advanced in understanding the science as compared with myself. Please forgive me but I fail to understand your explanation. At the risk of demonstrating my ignorance, please allow me to explain my own understanding.
You are quite correct in stating that the MES molecular subtype appears to be much more susceptible to DC VAX efficacy. This was suggested in previous studies in re UCLA for example. The reason suggested at the time was that MES was more immunogenic and had a greater heterogeneity as opposed to other subtypes such as, for example, proneural. In this regard, MES was likened to melanoma wrt degree of immunogenicity. These studies did not address either methylation or IDH status whether wt or mt. Rather, the explanation was, to the best of my knowledge, predicated upon the finding that MES, apparently in general, had a higher residual level of T-cells and the micro-tumor environment was less immunosuppressive. Accordingly, the combination of SOC and DC VAX suggested superior efficacy. This was due to the fact that there were more T cells with which to build upon plus greater time for tumor infiltration and destruction due to a lesser immunosuppressive tumor environment. As you know, this finding resulted through the use of DC VAX as a mono therapy, i.e., absent a combination with a CI. Researchers were gratified by this finding because MES is a particularly aggressive subtype with a sharply attenuated survival timeframe, or so they claimed.
Here is where I become a bit confused. Apparently, DC VAX L is particularly efficacious wrt M+ MES which is characterized by IDHwt in addition to other signatures including NF transcription errors. However, methylation appears to signify a less aggressive character since the cellular repair mechanism is interfered with. In addition, a relatively recent abstract dated February, 2018, which you can find in the intro to the NWBO MB, suggests that proneural is M+(IDHmt) and methylated molecular subtypes appear to have a significantly longer survival timeframe as opposed to M-. Accordingly, it would appear that M+ MES with the IDHwt signature is less aggressive than would be the case if it were non-methylated. Indeed, this same abstract correlated MES(as well as classical and neural which was subsequently dropped as a separate molecular subtype) with the non-methylation grouping. Accordingly, in this grouping which has a demonstrated significantly shorter survival time, MES would be more aggressive. However, it is unknown, at least to me, as to whether M- MES is IDHwt or IDHmt. I would presume that it would remain IDHwt regardless of methylation status. The prior clinical studies did not address these details as far as I recall and even more recent articles do not appear to be clear on these issues. In this respect, I don’t doubt that my understanding might be faulty. I also seem to recall, that the large majority of MES is M+ and accordingly, the M- grouping may be composed largely of classical which is also IDHwt. It should be noted that Brad Silver’s GBM was M+ classical if I recall correctly. Accordingly, MES appears to make up a very small portion of M-.
In any event, bottom line, the points I am struggling to make are:
1. In the case of MES, whether M+ or M-( which is relatively small), CI’ s are not required and DC VAX can act as a mono therapy adjuvant. This is because it is immunogenic or at least relatively more so than other subtypes. MES itself is a rather large subtype comprising anywhere between 30-50% of all stage IV glioblastoma. Hence, DC VAX appears to be significantly efficacious wrt at least one large and relatively aggressive subtype. This alone would merit approval.
2. In addition, DC VAX appears to have some degree of efficacy with respect to classical which is characterized by IDHwt and the over expression of EGFRviii. Classical appears to comprise about 50% of nGBMs and so DC VAX appears to be efficacious with at least 2 out of three major subtypes as a mono therapeutic adjuvant. Perhaps, it might be even more effective in combination with a CI because classical may be less immunogenic and have a more immunosuppressive micro tumor environment whereas CI could apply the brakes thus allowing more time for T cell, etc. infiltration.
Accordingly, the tail would not only be long(I have estimated at least 20% survival at the 5 year mark) but robust as well as per the above analysis.
Wrt to rGBM, DCVAX should be particularly effective since there appears to be a shift toward MES upon recurrence which appears to be much more aggressive. Is this now a morph to M- MES where survival is a much shorter affair? Since there have been extremely limited resections associated with cross overs, the success of DCVAX L would depend upon whether the original cancer contained MES. In that case, even though there would not be a new lysate, the rGBM endpoint might be achieved regardless because of the tendency to morph into MES upon recurrence.
Based upon this rather cursory analysis, I believe the results will be significantly positive and underscore DC VAX as an integral part of GBM SOC as an adjuvant mono therapy or even combinational approach. It may be the case that wrt GBM, combination with CIs may be relatively de minimus relegated to the relatively small proneural sub group. It may be this possibility that keeps BP up at night and “employee” short tenure visits to NWBO.
We live in interesting times.
All IMHO.
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