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Thursday, September 13, 2018 5:07:08 PM
you wrote:
5. So we have three pieces of information that show the first 38 enrolled did not do well.
6. The premise to this, as posited by you, is that they were primarily MGMT unmethylated. We can't prove this but there must be a reason. -- flipper
Could the White Blood Cell count have something to do with it?
Perhaps the early patients had relatively severely depressed levels of WBC? -- Evaluate
I think if you tracked the WBC content in patients over time, you might find that the first 38 were, as you say, severely depressed after their chemoradiation completed but before their DCVax-L therapy began. This inclusion may have been due to a multitude of factors.
1st. That is what chemoradiation does.
2nd. I'm no expert here, but it could be back in 2008, extracting "baby" monocytes to manufacture DCVax-L might have been less efficient than now days. Why do I say this? This is kind of an amusing story, so try to ignore my ramblings, but I'll get to the point. Back in 2014, when Dr. Bosch gave the excellent (also on webcast) presentation in Germany, he opened up his talk to questions. (A big "no-no" in NWBO land.) Some fellow who sounded like he had a fake German accent ( I may be wrong)(AF stated he was not in Germany at the time, but this had been one of rallying cry topics for some time.), asked about whether or not NWBO was having difficulty getting enough material from leukapheresis. Dr. Bosch, as I recall responded that was no longer a problem. Soak that in for a moment. Now recall, leukapheresis is a safe and efficient procedure for collecting large numbers of peripheral blood monocytes and different lymphocyte populations.
OK, if you are still with me, remember also, Dr. Bosch learned over time, as did the scientific world, you don't need large individual doses of dendritic cells to be effective. In fact, you need less than most people thought per dose in order to invoke a little known phenomenon known as dendritic trains, which is basically that instead of dying on the injection site, if a small enough number are injected, they form migratory "train cars" if you will, and successfully head off to the lymph nodes with their messages in tact. OK? RK was one of the people that thought the screening halt might have to do with leukapheresis needing to be performed more than once.
Now I have to give you more backstory. Anyway, going even further back, there was a company that was attacked, I think it was Dendreon, by a scientist/short that wrote a paper saying a trial was fixed because the control patients had WBC (white blood cells) extracted via leakapheresis but not returned, whereas the treatment patients had their DCs returned. She got in trouble for not disclosing, shorting to manipulate, and ultimately her argument was discredited, but I think it left its mark. Now, go back to the DCVax-L design. The leukapheresis is done for "baby" monocytes only. The remaining WBCs are supposed to be returned. However, the PBMCs are kept until later used as placebo or dendritic cells. Some are transformed into dendritic cells via the manufacturing process.
That seems like enough information. Let's go back to the first 38. It is possible that leakapheresis + TMZ + radiation might take WBC counts below what would otherwise be acceptable for immunotherapy if the early days of manufacturing required too many "baby" monocytes and did not return enough lymphocyte populations. I'm not saying that did happen, but it is possible, and as you know, NWBO made a big deal about WBC counts effecting overall survival and that this would be part of the endpoint analysis as a consequence of changes in trial design made in 2014.
Coming together? So your point may be well taken. Now let's return to what may be the pattern if we accept that the first 38 patients might have only had 1-3 patients live beyond 36 months. They really weren't all from a decade ago, as the article states, but they were from the earliest enrollment.
What happened after that? BY October 2015, long after changes were made to the trial, it seemed like everyone was living longer, in the immortal words of Dr. Liau. Oops. Overshot, but what did we learn. Well Dr. Prins was clearly trying to figure this out, because he came out with a paper that stated increasing the lymphocyte population in patients mostly helps dendritic cell therapy patients as opposed to SOC patients. However, what did we see? It seemed like everyone was living longer than expected, which would make the trial last longer. However, as we can tell from the KM curves in the Journal, not everyone is living a lot longer, so perhaps some were living than expected by a small margin, but finally a significant number -- say 30% -- were living much longer than expected. Still the trial was going to last too long, so the inclusion criteria started allowing patients with lower lymphocyte populations in to keep the trial length feasible. However, if it did help speed up the eventing in the trial, it did not do it in the 30% or more apparently impacted by DCVax.
Go back. Remember when I reminded you Dr. Bosch stated they were "no longer" having troubles obtaining sufficient quantities of monocytes?
Here is what may have happened.
From 2008 to 2009, patients may have had too many WBC lost to old leakapheresis + radiation + TMZ.
That may have been worked out by the time the trial restarted in 2011, and perhaps further worked out when the enrollment really started to takeoff in October 2012. By that time WBC was clearly on the radar. Perhaps quality control also slowly improved DCVax-L selection in the manufacturing process without materially changing the product.
Still, we have 65 investigators stating there was no change in survival based upon year of enrollment in a ten year old trial. I have to believe, that if Senti's count regarding lack of the first (undiagnosed MGMT) aka: 37 of 38 patients making it to 36 months, that the investigators must have meant, well, if you consider WBC and lack of MGMT diagnosis in the first 38, than they cannot be said to have changed the trend.
Something we must all remember, including NWBO (regardless if I'm right or wrong) is that most product manufacturing is improved during the clinical trials. It's not always a material change, and even if it is, it is does not always adversely effect the efficacy. In fact, a material change might improve efficacy, and then the regulators and company would have to look deep at whether or not this was kosher.
Let's look at Doc's premise (which I also used to hold and still toy with), that is NWBO was able to ameliorate the apparent efficacy change of an improvement made during the trial by adding sicker patients half way through the enrollment.
Using a recent post of mine, let's see how successful they might have been if I was correct about group ITT survival rates.
I basically concluded (based upon Senti's charts and efforts and other poster observations):
The first 38 did not do well by 36 month longevity standards. Only 1 to perhaps three survived beyond 36 months.
The next 144 patients did far better and appeared to have 28% to 30% surviving at 36 months.
I'm not really certain about the next 79 patients.
The last 70 patients enrolled appeared to be doing better (but this takes extrapolating data, something the Journal was not allowed to do) and they should at least prove to have 33% surviving as a blended group by 36 months -- but I think that might reach 39%
The final 31 enrolled appear to be all DCVax-L, and they might actually break the 50% median at 36 months if my calculations are close.
So does this fit Doc's hypothesis? Yes. It would explain why the survival kept increasing (but perhaps less so aka: somewhat camouflaged improvement) even after lymphocyte count inclusion rules allowed sicker patients into the trial.
Does it fit Meirluc's theory that it might be due to early lack of MGMT diagnosis? (That was weird, I just got a hang up call from Big Bear City, LOL) Anyway, it might fit his theory except, you would not expect the last 70 to increase as much as it did.
Does it fit RK's leukapheresis theory? Perhaps. It would account for the first 38, and incremental improvements along the way.
Does it fit Evaluate's theory regarding WBC? Not exactly, while it does fit the poor showing by the first 38 and the improved showing of the next 144, there is, however, the problem that it appears efficacy improved despite the second half of the trial including a broader swath of patients including those sicker patients with lower lymphocyte counts.
Les denies any major modification, but let's not forget Tumor flow filtration is something like a 17 year old patent NWBO has in its back pocket. Maybe he would not consider it instituting an improvement, but merely incorporating an already approved manufacturing technique to help reduce the chance of outside contamination. Of course it also can improve survival if utilized by reducing or eliminating the need for outside blocking agents to prevent premature monocyte development into the wrong kinds of cells. Let's look at what Cognate did recently. It joined forces with an outfit to actually replace TFF eventually with an even better technology. Sonic filtration. I'd bet you dollars to donuts this will help DCVax-L with future patent protection.
AF is a relic in many ways. But he is a great gate keeper of sorts for the old ways of conducting trials. That is -- one can't be flexible as you go. In immunotherapy this platitude is a death sentence to one or more generations of cancer patients. Immunotherapy is the manufacturing process. The scientists would take a hundred years to do what could be done in ten years if they aren't allowed to adapt, improve and tinker as they go forward in the clinical process.
To be continued.
Respect Risk. Conduct Your Own Due Diligence. Manage your assets wisely. Diversify.
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