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The P2 had a flaw in my opinion that the FDA probably would not have or did not approve for the P3. The patients started with VB-111 alone, and had a choice of crossing over from VB-111 to Avastin upon progression. Who do you think would be more likely to stay with VB-111... a patient that feels good or a patients that feels bad? That is a fundamental flaw making the results of that trial less meaningful.
I don't know if that flaw was deliberate to ensure good looking results regardless of efficacy, or whether it was simply necessary to attract enough patients for the trial, but presenting the results as meaninfull they do is misleading in my opinion.
Those P2 results do not foreshadow a failed P3... they just make it dubious like most P3's.
I don't remember if the P2 allowed patients to continue with VB-111 and add Avastin upon progression or if switching drugs was the only crossover option.
Countering this concern to some extent: Avastin is used for a lot of different cancers, just as VB-111 would be used in a lot of different cancers... if it helps. Avastin is one of the most lucrative drugs ever. It is the largest source of $ for the BP that owns it. Something that increases it's effectiveness would be enormously valuable if the patent duration is long enough to slowly feed it into all available indications.
Besides the P2 being fundamentally flawed, I am concerned that I have not seen the Ovarian P2 data. Maybe it will be PR'd today, but it was perfectly timed for an ASCO reveal, yet only P2 GBM is going to be displayed. Why? Did they do an NWBO and keep the P2 data for P3? Can they do that? It was open label... right? So... confusing to me.
This is getting mysteriouser and mysteriouser. And it sounds like you are reaching Flipper... but I like it! It is possible. It would make total sense. And nothing else does. Not even a scam quite fits all the clues... well... not sure there are any clues but if there were...
Never mind. Good luck to you longs.
Flipper, RK, Senti...
I am seeing a different Abstract Titles release date here than what has been posted a couple times. This may be something you are all aware of;
I haven't been watching closely. Or maybe I am misunderstanding something.
https://am.asco.org/abstracts
Key Dates for Abstracts
NOVEMBER 10
Abstract Submitter Launches
FEBRUARY 7 (BY 11:59 PM EST)
Abstract Submission Deadline
MARCH 16
Late-Breaking Data Submission Deadline (shell abstract must be submitted by February 7 deadline)
MARCH 20-21
Scientific Program Committee Meets to Select Abstracts
APRIL 3
First Authors Notified of Abstract Selection Decision
APRIL 9 (BY 11:59 PM EST)
Abstract Withdrawal Deadline
APRIL 20
Release of all Abstract Titles (Regular and Late-breaking), Accessible via ASCO's iPlanner website
MAY 17 (5:00 PM EDT)
Abstracts Released on abstracts.asco.org
AACR Panel Moderator:
Mr. Feuerstein; Regarding the possible outcomes in the cytokine war fought over the tumors: hopefully in some cases, a mass attack by DC's and their cytokines overwhelms the tumor's natural defenses even without Checkpoint Inhibitors. What are your thoughts?
Adam:
"Today’s weather forecast: 100% chance of a bio-turd equity shit storm. Take cover, immediately."
AACR Panel Moderator:
No... regarding the Cytokine war...
Adam:
I mean... "It's like shooting an elephant with a shotgun." Obviously a single large bullet would be more effective. I would recommend going with Celldex's GBM drug.
Insomnia and AD are likely tied. It is known that the accumulated misfolded proteins and other waste is normally expelled from the brain cells during a certain part of sleep. The brain cells contract dramatically opening the interstitial space, then the cells vibrate, allowing this waste to make it's way through the cell membranes into the lymph system where it is carried away. If you don't sleep, this cycle cannot happen.
This is a relatively recent finding. Why would 2-73 do this which it was not designed to do? Maybe there is a negative feedback where accumulation of this waste makes sleep difficult, so the patient accumulates even more waste, etc., etc., etc.. Maybe 2-73 breaks this cycle by reducing misfolding etc a little, which improves sleep a little, which reduces waste a little, which improves sleep a little, which reduces waste a little... etc., etc., etc..
It would be nice to know why, but as long as it is not placebo effect, and the effect is long lasting, then it is a big deal regardless of the mechanism. Assuming this is all real. It appears to be real.
Note that the misfolded protein segments that cannot be metabolized are shoved into the cell membrane by the cell. Maybe this shaking by the cell during contraction assists further migration into the interstitial space. No point in shoving the fragments into another, adjacent cell. Better to require this shaking which only happens when the cells are dramatically contracted.
Recently a few/several people have posted saying that OS best reach endpoint down the road. Has anyone been saying that even if OS has already met it's endpoint, their model says all could be well?
Seems to me that either:
1) the bears are right, or
2) price manipulation was tolerated or enjoyed or assisted to give Cognate cheap shares, or
3) the PFS data is not enough to put them over the top but there is reason to have some hope that OS will.
But if 3) then how could they reveal PFS data to investors if the trial is still blinded? The secrecy clause is no match for blinding requirements. I know others have pointed this out.
If 1) then the PFS secrecy clause is a head-fake.
If 2) then PFS and OS data might both still be good... and only 1 person was "shown the PFS data"...
If 3) then everything sort of makes sense, but only if OS as well as PFS already reached their endpoints. And they showed investors the not so great PFS data but refused to reveal the OS data. 2) would also require that both PFS and OS endpoints have been reached.
or
4) I am a moron to put helium into a turtles head.
Never mind.
Troubling times in the Queendom. I can come up with positive scenarios for the near future, but would I be haloing? Probably. Was the recent funding a last minute idea or planned?
If a last minute idea, did they finally get a whiff of the OS stats or PFS stats... and it was stinky, so there will be a delay, (or worse), to their progressively higher SP funding plans... (ie pfs ruled out more completely or PFS abstract rejected... so it is truly all OS now.)
or did they not get a continuance of the civil case so had to arrange for Cognate to get some cheap chairs to give back to them as part of the settlement...
or was there a whiff of results that had the smell of victory so this is a last ditch effort to shake all those retail fleas off of the big dogs?
I sure as heck do not know. But as much as I like dolphins and many other animals more than turtles the interday bottom in recent years was recently set at 22 cents which I must concede was a number predicted by a turtle about 9 months ago as I recall. I know I could be making a monster turtle, but hopefully it won't read this post.
I love the sound of that, however, I don't see CYNF ever existing as a company.
What you describe could absolutely be happening for AVXL. The sec reference to a vote (at the next annual shareholders meeting) to allow large financing if needed could be part of the chess game to up the anti for acquisition. But CYNF does not appear to have ever existed, so... why are you disseminating misinformation?
"DCVax-L stands out among the other DC Therapies". Doktornolittle, Feb. 22, 2017.
I would agree. My gut tells me that it is the best horse in this race.
"IMUC is rocketing" Cap of $8M and misunderstood news. The news was that the freeze company they are using finally finished their tests and they are now good to go (at least regarding freeze method) with the phase 3 trial which everybody thought started a long time ago. A trial which is not projected to end for many years.
I am not saying the technology is bad. I don't know. I think it actually might be good. But I'm not so sure about any of the technologies that rely on self antigens that are highly expressed on the tumor. And I think all of these 6 synthetic antigens for IMUC are self antigens, not common neo-antigens.
But the spike yesterday appears to me to have been due to a misunderstanding by hair trigger investors that they were announcing good results regarding their actual trial. A trial which hasn't even started yet. I think there will be a correction as the people that jumped in figure this out.
But again... it has a super low market cap, so I am not saying it is a bad investment. I am just doubting the news was worthy of that reaction.
Would the sponsor in a (still) blinded GBM trial get feedback on individual patient subgroup determination from biopsies? To be clear, I mean while still blind?
Not really a response to your last post, but wanting you Flipper to see the question along with others.
UCSF Doctors expressed feelings: I hope Flipper is right that the words said are what one should pay the most attention to. One thing that aligns with that is the following: When you are jealous of someone and you talk about them, you usually end up using a tone that is indicative of putting them down, even if what you are saying is not substantively negative.
My concern in this Cobb / Prados video is that I respect UCSF a great deal. I don't know about brain cancer specifically, but my understanding is that they are up there with Stanford, but with a little less money.
Then again, I am biased because I live in Northern California and I went to Cal Berkeley for my first degree, a Biophysics degree. But Cal has a strong rivalry with UCLA. Very strong. You should see the offensive tee shirts sold in preparation for the annual football game every year! This rivalry is second only to the rivalry with the local Stanford. Even USC is not scorned, for whatever reason, as much as UCLA.
UCSF does not have a football team. What they have is an outstanding medical school and hospital that is in competition with Stanford and UCLA. It would be totally consistent for these MD's to vent emotion regarding that rivalry without actually saying anything substantively negative. And maybe Flipper is right that this is all they do in this video.
AVII: Your expert is speaking English for us, but I think there is still some translation needed, provided below:
10:36) I have absolutely no idea what the data is showing for the DCVax-L trial, but I am going to proceed here to convince you that the data is bad. Please ignore the fact that I will show you that going after 1 antigen, my favorite approach, turned out to be disastrous while going after 6 antigens that are not even neo-antigens does seem to have some efficacy. So clearly going after scores of antigens, including neo-antigens will fail miserably.
11:00) There is a very good reason that NWBO cannot talk about the data (even if they know the data, which they don't). There is an increasing concern about disclosing data.
11:05) We all know that trial sponsors have access to unblinded data even before their DMC's and would publicize that unblinded data if it was good.
14:10) Celldex screened out 80% of patients for enrollment.
14:20) I was absolutely shocked that a trial based on a single antigen that is not even a neo-antigen failed miserably. This announcement was the worst day of the year for me. And I am considered a fgn expert in this field.
14:58) First Celldex reports that 26 of 32 progressed patients show none of the target antigen in the recurrent GBM. Then, beyond belief, they initiate a phase 2 for recurrent GBM "ReAct" using the same self antigen with no screening for patients that still show the antigen, and report the best results ever reported for GBM. Even more amazingly, instead of calling these guys out on what is obviously a repeat scam, "Re-Scam", I am very excited about these results, as are many charities.
????) That's it. He never actually gives any reason whatsoever to suspect that DCVax-L will not work other than the fact that the sponsor has not bragged about the results before the data is unblinded.
AND THIS IS ONE OF THE MOST RESPECTED MEN IN THE FIELD
HINT HINT!
"If there were institutional investors wanting to get in before positive news hits, there would be more volume."
Is that right? Is that when the big dogs go in, when there is no volume? You should do an investment thesis based on that.
They are not seeing much in the MRI's is one possible take from what they said. But go back to 58:30 where one researcher talks about how GBM itself can often not be seen in the MRI's when it is dispersed.
I agree that the mild bashing was disturbing. But comments others have made about competition, even among very good people, is real.
Eons ago I built a gadget at night at work to allow our MRI system to warm up faster. It was a resistive MRI magnet, not superconducting. One of the Ph.D.'s volunteered to test it. I let him, since I did not have my MRI pilots license... and he lied and said it didn't work. He was sure it would create excess noise, and he showed me the test result, which showed no measurable noise. That was all he had printed out. He didn't bother to hit the second key to print out the parameter involved in warm-up. One fkn key. But he assured me it had not worked. Knowing that the data stayed on the computer until the test was repeated, I tried to get him to print it out later, but he found a way out of it every time. Needed to go to a meeting, etc..
A year later the company got it's back to the wall and needed that gadget badly. They needed it as standard equipment on their new mobile systems where warm-up time is more critical (and where one of the VP's screwed up and advertised an incorrect start-up time). And he knew this, but he said nothing. I finally had to chess game my way around him. I was successful in doing that, and the device became standard production. First test on the mobile system was a 10 fold reduction in drift. In the end it wasn't really that good, but it was pretty good. It definitely worked and that researcher definitely lied. (I knew that he had lied from day 1). And this was a great guy. One of the best men you could ever meet. He tarnished himself that time, but it was out of character.
The possible similarities to this situation are very strong. Good guys, but maybe bashing something good. And specifically the shock they express that the therapy does not create side effects. But these efficacy test results are not in their hands, as in my case.
As Highwayman said, all they know is that they have not seen pseudoprogression, as they would expect. But how much pseudoprogression did LL report in the early studies, and how many patients have these guys seen? Not that many it sounds like. Doesn't sound like a solid basis for criticism given the low number stat basis.
But I hear you. The discussion got to me. I see why you would smile and embrace everything negative that they say. And you might be right. They might get their wish. You might get your wish. Make a wish!
Yeah, I over-reacted. It's potentially as little as a couple of weeks later than I thought might happen. Not a big deal in the big picture.
Ok. Good. But I think many, including myself, thought the review was already in process.
So your sayin' there's not a chance? Ouch. I will have to wait for Sentiment to fence with you, but ouch!
"I am surprised at the very low volume on this stock." Yes, very bazaar. Calm before the storm? Eye of the Hurricane? ????? I am hopeful with Sentiment and others that the UK eval is a major catalyst. It could also be a disappointment. And it could be nothing. But the chances that it is something, and something big are high enough that you would think there would be more jockeying for position one way or the other. But nothin.
"every small bit if detail" The significance of the screening hold is not a small detail. The company presented the FDA lifting the hold as a change in heart by the FDA. The broader investment community did not buy it.
It's a very big deal. If the FDA really did have a change of heart, that would be an enormous boost to confidence in the stock, just as it was perceived as an enormous negative when the hold was imposed.
However, it is very possible that the removal of the hold was as significant as the company would like us to believe, but because it is a reflection of the FDA's estimate, perhaps from a distance, of efficacy, it is a topic they choose not to attempt to address at this critical time in the trial. Maybe they don't want to walk that line. That is how us longs have rationalized much of the long silence, so it is just one more thing to rationalize. I would agree with that.
But that this is just a trivial detail... no.
While your talking to Les, it would be nice to get a clarification about the significance of the FDA lifting their screening hold. Was that really a change in heart by the FDA, or was it a trivial move that was hard-wired into the original halt; ie to end at some point after it becomes moot.
This non-invasive method to identify mesenchymal based on MRI scan analysis sounds great. A non-invasive method is ideal, but this method would be for future use, not for analyzing accumulated MRI data for the trial. That is, unless they planned on this from way back. (The article is 2013) At least some of the scan types they describe are special scans, not just special post analysis.
New territory. What was the plan for Celldex's product for the classical group? Micro-array analysis to identify that subgroup? If agreed with the FDA, then that is the fall-back for NWBO on mesenchymal, if necessary. But to have a non-invasive method for full scale (after approval and ramp-up) patient screening would be fantastic. Hopefully the same method could give further identification beyond mesenchymal.
Then heterogeneity rears it's head. Maxwell Smart's Chaos. But sometimes they have to plod forward with imperfect models to make progress. Hopefully the subgrouping (4 subgroups) that they have done will be a useful enough model to allow progress.
Corrected: "48.84% Mesenchymal for GBM"
(Article said GIMP Negative GBM 40% methylated... not all GBM.)
This number and other important stats must be highly radioactive because they have a very short half life in my brain. If so, maybe putting a critical mass of these stats in one place will evoke a brilliant flash of insight... like Jim on "Taxi" used to have.
Mesenchymal = 48.84% of GBM
Classical = 25.89% of GBM
Neural = 12.00% of GBM
Proneural = 13.26% of GBM
Mesenchymal = Predominantly unmethylated
Classical = Predominantly unmethylated
Neural = Predominantly unmethylated
Proneural = Methylated
GIMP Negative GBM (Mesenchymal+Classical+Neural) methylated: 40%
Inferred GBM overall methylated: 48%
Methylated GBM survival advantage with TMZ vs w/o TMZ: 6.4 months.
Unmethylated GBM survival advantage with TMZ vs w/o: 1 month.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995672/figure/pone-0094871-g004/
Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347445/
KeyChrt: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347445/figure/F1/
See also post Post # 101367 mostly replicated here.
"48.84% Mesenchymal for GBM"
This number and other important stats must be highly radioactive because they have a very short half life in my brain. If so, maybe putting a critical mass of these stats in one place will evoke a brilliant flash of insight... like Jim on "Taxi" used to have.
Mesenchymal = 48.84% of GBM
Classical = 25.89% of GBM
Neural = 12.00% of GBM
Proneural = 13.26% of GBM
Mesenchymal = Predominantly unmethylated
Classical = Predominantly unmethylated
Neural = Predominantly unmethylated
Proneural = Methylated
% GBM methylated: 40%
Methylated GBM survival advantage with TMZ vs w/o TMZ: 6.4 months.
Unmethylated GBM survival advantage with TMZ vs w/o: 1 month.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995672/figure/pone-0094871-g004/
Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347445/
KeyChrt: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347445/figure/F1/
See also post Post # 101367 mostly replicated here.
I had to read your message a couple of times to appreciate what you are saying. But I get it.
For anyone who did not follow: They believe that if DCVax-L gets approval in Germany that the Germans will immediately talk to Linda Liau/Prins et al and ask for the latest and greatest recipe that is based on DCVax-L and quickly run a single arm study to allow upgrading DCVax-L to account for everything that has been learned since the long trial started. Sounds like they anticipate some faith given to the UCLA team in allowing such with a single arm trial. They were also pointing out that policies in Germany allow a lot of leeway for doctors treating patients, making all this more likely.
This in response to my saying that I thought it is possible that dropping TMZ from protocol for Mesenchymal patients might improve their outcome
(if heterogeneity does not allow non-methylated classical components to escape)
If they do end up going with biopsies up front and can confidently determine mesenchymal and (more difficult) rule out any methylated components in the mix that might respond to TMZ but are likely resistant to DCVax-L).
------------------------------------------------------------------------
Not sure about German vs EU policy at this point, it has been a while since that was in discussion. I have forgotten. I know the Germans are highly respected and their Hospital Exemption program is their own, not EU wide... so they do have some of their own policies...
All in all, I like what you are saying and hope that is the case. It would make a lot of sense to me to give the researchers that put forth a therapy to update it upon approval with minimal red-tape.
This 2013 article addresses many of the questions that I have been struggling with today. I will probably forget all this and post the same chart next year... but today I will see clearly. Of course other data is available from other articles, but I am happy to accept all this info as the real deal.
Article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347445/
KeyChart: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347445/figure/F1/
Putting info together from throughout the article and the chart:
% GBM methylated: 40%
Methylated GBM survival advantage with TMZ vs w/o TMZ: 6.4 months.
Unmethylated GBM survival advantage with TMZ vs w/o: 1 month.
Chart states that mesenchymal is predominantly unmethylated.
So... I would argue that the mesenchymals would do better without TMZ when an immunotherapy is being used since TMZ weakens the immune system, at least temporarily.
Maybe the DCVax-L protocol adresses this fully, maybe not.
I think I understood LL saying that this issue is not understood well enough to risk stopping TMZ (from the beginning) for ie mesenchymals. But realize trial protocol was setup a long time ago, and to some extent she may be defending that protocol. It could be in the end that tumor heterogeneity begs the use of TMZ even for mesenchymals, neural and classical types, all of which are predominantly unmethylated according to the above chart, but I think that has yet to be seen.
I am just saying at this point that it seems likely that however effective DCVax-L turns out to be for mesenchymals, it will likely prove to be even more effective when TMZ is dropped. Likely, not certainly.
Thank you Longfellow. Sorry Sentiment. So IDH1 type and methylation are distinct characteristics. I worried a little that they might be. I was oversimplifying. Much to learn and an absolute pain deciphering this stuff. As you say Longfellow they don't relate this to the four subgroups that we are familiar with. The article does not show a date, so it might pre-date those subgroup identifications. One can guess some of how that panned out, but the info is probably out there so better to just research it. I guess I have an obligation to do so now.
Very good article. Thank you.
One side piece of info was that (at least at the time of the article, and probably still the case) it did in fact take a tumor biopsy to determine methylation.
---------------------------------------------------------------------------
Quote:
Discussion
GBMs are extremely heterogeneous tumors with multiple complex genetic abnormalities. Among various prognostic biomarkers, IDH1mutations appeared most important and defined a distinct subgroup of GBMs with favorable outcome [18], [19]. Similarly, the present study also highlighted the prognostic significance of IDH1. However, other molecular genetic alterations, namely, TP53 mutation, NF1 mutation, EGFR amplification, and PDGFRA amplification, did not demonstrate any significant association with survival in the IDH1 wild-type group. MGMT promoter methylation status has been one of the well-known positive prognostic as well as an independent predictive marker for therapeutic response to TMZ in high-grade astrocytic tumors [6], [20]. Its relevance for prognostication of GBMs was also confirmed in the present series. TERT is another frequently mutated gene in GBMs with prognostic implication. In the present study, the frequency of TERT promoter mutation was slightly lower as compared to the reported Western literature. However, similar to previous studies, this genetic alteration was found to be significantly more frequent in older adults as compared to young adults [8]. Hence, the lower frequency of TERT promoter mutation in the present series may be attributable to the lower mean age of our cohort. Our data also showed that TERT mutation was associated with poorer outcome in GBMs, consistent with previous data on gliomas [12].
Few studies in recent years have prognostically stratified GBMs based on combination of various biomarkers. Interestingly, all these studies included IDH1 mutation in the marker panel for prognostication. Based on the IDH1 and MGMT status, Molenaar et al. [11] stratified GBMs (n-98) into three prognostically different subgroups. Patients with IDH1 mutation and MGMT methylation had the longest survival, followed by patients with IDH1 mutation or MGMT methylation alone, whereas patients without both these alterations had the shortest survival. Similar prognostic stratification using MGMT and IDH1 was also described by Hartmann et al. [21] in cases of high-grade astrocytoma (grade III and IV; n = 338). Interestingly, the authors did not observe any significant difference in prognosis between IDH1 wild-type GBMs and anaplastic astrocytomas. Killela et al. [12] analyzed IDH1/2 and TERT status in 415 cases of gliomas of different grades and showed that, based on these genetic alterations, grade III and IV tumors can be effectively classified into four prognostic subgroups irrespective of tumor histomorphology and WHO grade. The cases with both TERT and IDH mutation (morphologically oligodendroglioma) had the best prognosis, whereas cases with only TERT mutation had the worst prognosis. Interestingly, within the GBM group, concomitant IDH and TERT mutation was extremely rare. Hence, GBM cases were subdivided into three prognostic subgroups. Cases with only IDH mutation had the best prognosis (OS = 42.3 months), followed by cases with IDH/TERT wild-type (16.6 months) and only TERT mutation (11.3 months). Recently, Eckel-Passow et al. [13] subdivided 1087 cases of gliomas (615 grade II or III and 472 grade IV) based on IDH, TERT, and 1p/19q co-deletion. Among the GBMs, majority (74%) showed only TERT mutation, 17% were triple negative, 7% had only IDH mutation, and only 2% showed combined TERT and IDH mutation. Similar to the previous studies, cases with only IDH1 mutation had the best and cases with only TERT mutation had the worst survival.
All the above-mentioned studies including ours highlight the importance of IDH in prognostic stratification of GBMs. Unfortunately, IDH1 mutation is rare in primary GBMs and seen mainly in secondary GBMs which constitute only 10% to 15% of all GBMs [22].On the other hand, there is considerable heterogeneity among the IDH1 wild-type cases in terms of clinical outcome, indicating the necessity of further stratification. For the first time, the present study demonstrated that IDH1 wild-type cases which constitute majority of GBMs (approximately 83% in present series) can effectively be subclassified into three prognostic subgroups based on MGMT and TERT status. Interestingly, IDH1 wild-type cases with only MGMT methylation (group 1) had survival similar to the IDH1 mutated cases, whereas IDH1 wild-type cases with TERT mutation demonstrated worst survival. IDH1 mutated cases need not be further stratified based on MGMT and TERT because majority of these cases are MGMT methylated and rarely have TERT mutation.
Therefore, based on the results of the present study, we recommend routine assessment of a panel of only three markers, namely, IDH1 mutation, MGMT promoter methylation, and TERT mutation status for GBM prognostication. All cases of GBMs should be analyzed for IDH1mutation first by Sanger sequencing or immunohistochemistry with mutant-specific antibody followed by assessment of TERT and MGMT status especially in IDH wild-type cases. All these assessments require a small quantity of tumoral DNA and can be done on DNA extracted from FFPE tissue. The International Society of Neuropathology-Haarlem Consensus Guidelines state that “It is also entirely possible that genetic tests not discussed at this meeting (eg, TERT mutation) will be incorporated into diagnostic definitions at the time of the eventual WHO classification revisions” [23]. Our study thus supports the incorporation of these tests into the final revised WHO classification. prognosis
"I'm not sure if I've mentioned this to you or not, or if you already came across this... but in this video where LL is answering questions with Dr. Cobb, she states that it is the IDH1 mutation negative wild-type tumor that does well on DCVax-L."
Yes, that is the part of the video that I point to in my three recent posts. Starting at 48:10. But stated it in that fashion is not very useful for about 99% of the audience, and even confused LL, as I pointed out.
So I attempted to translate that, and was asking for verification that I translated it correctly. I would appreciate it if you would double check this, but:
1) Wild Type = prevalent genetic type
2) Not 100% certain whether methylated is more prevelant than unmethylated, but this study below observed 2/3 unmethylated, 1/3 methylated, so I am going to assume that unmethylated is generally considered wild type.
https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-10-36
On the other hand elsewhere in the report they say that methylation is reported in 30-60% of glioblastoma patients. Best guess from that is 45% which puts it awfully close to 50% which makes the term "wild-type" pretty useless and therefore inappropriate because wild vs not is purely a statement about prevalence. Still, even in this statement they are giving a slight statistical edge to unmethylated, so I will continue to assume that the wild type is unmethylated even though I do not understand why they just wouldn't spell that out.
So LL then stated that the mesenchymals are primarily unmethylated.
But please do check my reasoning and facts here.
Corrected: I meant Mesenchymal not Methylation (not sure status can be easily determined even from a biopsy)
For years I have been waiting for a statement from an LL type that clarifies whether methylation status can be determined from any patient tissue, or whether it has to come from examining the tumor... and you are right that this was not resolved by LL's statement that it is now a common procedure.
However, I am guessing that the tumor usually has the same methylation character as the rest of the patient tissue/dna so the test can be done with some confidence before / without a biopsy. But even if it takes a tumor biopsy, I think I am hearing that such biopsies are now common.
Not sure that mesenchymal status can be easily determined even from a biopsy, however. If so, why would LL talk about how easy it is now to determine methylation status but not mention easy determination of the 4 subgroups in the same discussion.
As for the heterogeneity of the tumor types... I remain in denial about that. If that were generally true then there would be no such thing as the 4 subgroups and no benefit to trying to specify a given treatment for a given subgroup. There may be heterogeneity given there are reportedly scores if not hundreds of mutations for each tumor, but I do not want to believe, and do not believe, that sufficient genetic heterogeneity to properly be described as mixed subgroups is common.
RK: In this video LL states that Avastin (Bevacizumab) works by degrading blood flow to the tumor. I'm not sure where you found those articles that say that it works by increasing oxygen to the tumor thereby decreasing the immunosuppresive response by the tumor and otherwise increasing the viability of the immune components in the tumor environment... but I am going to believe LL.
Seems to me that if DCVax-L does not reach the required efficacy bar for full approval for all subgroups, then it might be the unmethylated population that it gets approved for. This is 180 degrees from what I used to think.
If they can identify mesenchymal or not soon enough, then of course we all hope they can get approval for all mesenchymals, methylated or unmethylated.
Combined; All unmethylated + all mesenchymals = a large percentage of patients.
But it is still not clear whether they can identify the mesenchymals soon enough to effectively steer them to DCVax-L. LL never says that they can, while in the same discussions she says that they can identify methylation status easily.
What percentage of those classicals that respond well to TMZ are methylated? Probably all of them.
My point is that DCVax-L was probably not given a fair test regarding the mesenchymals since they all got TMZ co therapy and yet the majority probably did not benefit from it while they certainly got some degree of immunosuppression.
Methylated patients do better in general apparently because they respond better to TMZ (maybe also to radiation). So methylated mesenchymals doing better would not be a surprise. But according to LL, the mesenchymals are disproportionately unmethylated.
I am not suggesting that they remove TMZ from mesenchymals, but rather, from all unmethylated patients, which would apparently include the majority of the mesenchymals.
And they do have a good way to detect whether patients are methylated or not according to LL. A method that is now in common use. Not sure they used to have such a method back when the TMZ label was granted eons ago.
Mesenchymals mostly unmethylated? That is what I think I am hearing from LL starting at 46:35 in this excellent video that was posted yesterday (maybe posted prior also but that was the first time I saw it).
Good stuff! Absolutely worth a listen. Dr. Cobbs meandering alone answered a large number of long standing questions I had about GBM and cancer in general.
"Later on, they review the MRI and determine that that pt had a psPD event and shouldn’t have crossed over. They can’t un-crossover that pt so what do they do? Eliminate that pt from the calculations? I’m just not seeing it. However, I don’t have these type concerns to begin with since multiple scans are used before a pt is determined to have progression."
You weren't talking to me, but I had speculated about this earlier. I agree that it would be a mess if they changed their minds about previous progression determination. There is a strong need for that determination to be set in stone before crossover. So my speculation about employing a new and improved method for determining progression including distinguishing pseudo, in the post analysis, is dubious, as many have pointed out including AVII and Reefrad, and to some degree yourself here.
However, while there is a strong need to nail down progression before crossover, there is even a stronger need for an effective treatment for GBM. I would argue that however messy, if post analysis of progression using a new and much improved method, based on existing MRI scans, reveals remarkable efficacy, then I don't think they could ignore that. Shrugging formalities is dangerous in part because the statistics underlying those formalities is not transparent to most. But if people that do understand the basis for those formalities can see that they are in this case blocking the approval of an effective therapy... then they should have the power to push a drug through to the point of being profitable for a company to produce so as to move to confirmation. And that is what various early approval modalities are all about. Including one that has been talked about here recently and may well be currently under review. I will not say much more until Sis gets in.
The FDA is absolutely obligated to prevent another disastrous Thalidomide indication from happening, as are all regulatory agencies around the world. But this is certainly not another thalidomide, so non-linear thought is likely allowed here, even if NWBO did not say, "Mother May I" before curing brain cancer.
Ok. Those were this morning. Farther back than I looked or searched. I think those criticisms should be expected. Others here, including myself have pointed out the same ambiguities. If the lift on the hold is the real thing, then NWBO needs to spell that out.
But let me give an example of a possible reason why they cannot speak about it, (so the halo does not dim for me). Just one of infinite possibilities:
The original hold was due to an apparent PFS futility that was based on dated technology for determining PFS. But the sponsor was still blinded when it subsequently specified a new and improved method, which is in fact universally accepted as more accurate and more appropriate here. That new and improved version was used recently when determining the PFS count, and the FDA learned something about efficacy at the same time, responding, "Holy Mother of God, this is a true miracle. Let us not sit on this struggling biotech any longer, but free it from our errant curse immediately!" And so it was done.
However, the FDA was not speaking out loud above. They just mumbled it to themselves. So the trial sponsor, and all of us, remain blinded.
Although just one of many possibilities, I'm pretty sure that is exactly what happened.
Nope. At least I don't see it. Quote it so I can find it. Just a short phrase would be enough. A search for $NWBO gets no hits.