UK Independent Television News, 22.30hrs, Sunday, 22nd November.

All that is missing is the name and developer of the vaccine. In the meantime and in the continuing absence of Top Line Data and approval for DCVax-L, Silver Disc, anybody?
To sample click here

Umibe san, it's been a long time, isn't it? Did you come here with good luck?

Dear Karl,

I regret that I don't understand the question nor the 2 questions that follow, so that I cannot give you an answer. Sorry.

Evaluate,

Yes. I don't see any reason why not.
I have no idea but logically it should be more effective than vaccine made from the original tumour which has since mutated and which has now clearly escaped from control by the original DCVax-L.

A group at the Jonson Comprehensive Cancer Centre working with UCLA. They are comparing DCVax-L with DCVax-L + Opdivo (nivolumab) in recurrent Glioblastoma. The clinical study identification is NCT 03014804

Karlchen, I have no specific knowledge about recurrent glioblastoma after an initial response to DCVax-L, but logic would strongly suggest that the recurrent tumour has undergone a mutation - in fact probably many. The fact that the tumour initially responded to DCVax-L indicates that the sensitised dendrocytes in the vaccine (and, consequentially, the T-Cells) were originally able to gain access to the "malignant epitopes" (i.e. those epitopes which were expressed only on the malignant cells in the tumour) and thence to kill the malignant cell.

Because the recurrent tumour developed from the remnants of the de novo tumour (against which the DCVax-L was active) the recurrent tumour will still be expressing some/most/all of the malignant epitopes against which the dendrocytes in the DCVax-L were sensitised. The fact that the sensitised T-cells can no longer kill the tumour means that they either cannot physically latch onto the malignant cell (possibly because the malignant cell is secreting a chemical into the local milieu which disrupts the process of latching), or despite latching onto the malignant cell the T-cell can no longer gain access to the interior of the malignant cell to begin the process of killing it because its entry mechanism is being blocked. In other words, the tumour has developed a blocking mechanism, aka "a checkpoint".

To overcome that it may need something as simple as adding a checkpoint inhibitor (if the checkpoint is identified and an inhibitor has been developed) and that approach is, I understand, already being investigated (but not by NWBO).

Of course it would be best if sufficient recurrent tumour could be harvested so that a new DCVax-L could be produced and given with or without a checkpoint inhibitor or any other therapy.

More than 1 belt and several pairs of braces (aka "suspenders") are nearly always preferable in cancer therapy.

Happy - Live up to your monicker - the only thing that is currently slowing the process is the analys of the trial data - something which is in neither the UK's nor NWBO's power to influence.

Don't jump the gun before scattering derogatory aspersions. Wait until TLD is announced then start the countdown to see whether the UK is slow in deciding whether to allow the use of DCVax-L or not.

You characterize the slowness of the FDA as being "bad news", adding that the Europeans "do tend to take forever and cannot be trusted anymore than the FDA can".

The UK has already fast-tracked DCVax-L (a couple of years ago) and I have no doubt that when the results of the trial show that DCVax-L works it will be speeded through to acceptance a.s.a.p. Were the FDA to be tardy, there will be severe public pressure placed upon it to follow suit with the UK/Europeans.

That is hardly bad news - bad news would be if the trial failed.

I do not recall the earlier posts to which you allude but with several hundred messages being posted each day on this board, that is not surprising.

HL - do you honestly believe that the UK and European Regulators will sit back and await a decision from an FDA which is dragging its feet (either intentionally or because that is the only speed it CAN go).

Of course not. They'll licence and then advertise in the USA that they are open for business.

The inevitable result of the FDA not agreeing to a change in the endpoints whilst the UK & EUA do agree to the change - thereby licencing DCVax-L for use in the UK & EUA - is the growth of medical tourism from the US to Europe for treatment of glioblastoma. Sadly, that will probably be only for the rich as US Insurers would be unlikely to agree to foot the bill.

Eventually, in the light of experience and public pressure in the US, the FDA will have to climb down off its high horse and licence DCVax-L for use in the US.

Nuffink to do wiv me, Squire. Oi tink you've clicked on the wrong link.

Thanks, Mani.... If staying at a Holiday Inn gives one such insights into future stock market trends, I'll have to spend a bit more time on vacation.

As I am ignorant where such matters are concerned, how do you know this to be the case?

Hansm, I think that you may be under the misunderstanding that "SeekingAlpha" was the author of the report that you quote. SeekingAlpha is just the platform for other's articles.

The figures that KAM quotes were from a piece by Bohsie Research published in SeekingAlpha on 9th October 2020. Bohsie Research has published 4 reviews of NWBO in SeekingAlpha, the first one in 2013. None of them were dismissive of NWBO. The nearest the author came to a negative review was in August 2017 which included the following:

Just the sort of opinion I like to read first thing on a Monday morning - it makes my week!!

Thanks, Pterion (and you other repliers), for answering the postulate that any increase in survival in this trial (as compared to historic survival numbers when SOC alone was used) might be due to greater competence of the participating surgeons.

ahp123, your point is irrefutable - better results may simply reflect better surgical techniques being used by better surgeons participating in the trial. If that were to be the case, the only thing that you could say about this trial is that even though DCVax-L might not have prolonged life (as it might superficially have appeared to have done) it did not shorten life (from toxic effects) or reduce the quality of the remaining life (from toxic effects).

Despite this, if the Regulators in the UK, EU and USA passed it for use in their jurisdictions and it became the SOC in the surgical practices of all neurosurgeons (the good, the bad, and the indifferent) in those jurisdictions it will soon become clear whether DCVax works or not. This will be especially so if there is adequate "post-marketing surveillance" which would be facilitated by the personalised nature of each dose produced.

At worst the survival figures following SOC with DCVax will show no improvement over historic SOC alone and the hopes that the treatment heralded a new dawn in the treatment of GBM will gradually fade away and DCVax will become just a footnote in history.

However, if it turns out that SOC plus DCVax produces better survival figures than historic SOC alone for all surgeons (irrespective of competence), all GBM sufferers (and not just those lucky ones chosen to be in the actve arm of future trials) will have been given the chance of a reprieve.

There is one certain conclusion to be made from this trial and that is that there can be no justification to run any more placebo-controlled trials of the DCVax platform because of its lack of negative effects on the quality and duration of life.

PHEW!!! Thanks a million, Tryn - that puts my mind nearly at complete rest!!
If the European Regulators approve the use of DCVax-L based on the amended statistical analysis I would be more than completely surprised were the FDA not to follow suit.
If the European Regulators approve DCVax-L and the FDA did not approve it, I have no doubt that passenger numbers on transatlantic flights would show a significant upturn thanks to medical tourism from the USA to Europe. (It might save quite a few jobs in the aviation business.)

Iwasadiver, I hope that I am barking up the wrong tree in my understanding of several observations / claims made on this Board over the last 24 hours, so I would appreciate it if you (or anybody else) can tell me whether or not my uderstanding (below) of the new position is correct or is a total misunderstanding? (I hope the latter.)
As I understand it,
1] The changes to the Statistical Analysis are on a European Union website which has no connection with the FDA in the USA and the FDA is not bound to accept anything that the European Regulator decides.
2] The changes to the original Statistical Analysis are entirely of NWBO's doing and the European Regulator had no input into the changes.
3] There is nothing to indicate that the European Regulator must accept these changes to the Statistical Analysis or has already accepted them or would accept them in the future.
Many thanks for your help.
Doclee

If Mrs Powers wanted to kill the shorters, how might she go about doing it?

How about:
1] Indicate that something might be wrong - such as by missing the firmly forecast deadline for TLD
2] Do this a day or so before the markets close for the weekend
3] Shorters go into action and drive price down expecting an easy kill
4] Management announces a successful TLD just after the markets close on Friday
5] Shorts sweat out a bad weekend before finding the SP is climbing vertiginously first thing on Monday morning as the big money pours in.
6] Shorters have their fingers badly burned and crawl away cursing.

Sound familiar??

It reminds me of what Humpty Dumpty said to Alice in "Through the Looking Glass";

And just who are "Medical Research Collaborative"?

Theoretically, the vaccine should be effective in all cases of GBM because the dendritic cells have been sensitised to all the malignant epitopes being expressed on all the cell surfaces in the resected tumour. Although later mutations in cells not removed at surgery can cause the apperance of new malignant epitopes to which the DCVax will not respond, that should in no way affect the activity of the vaccine since the original malignant epitopes will still be expressed by the multiplying malignat cells.

The fact that it doesn't work in all cases is probably due to some malignant cells expressing one or more epitopes (known as "Checkpoints") which bind with and over-activate part of the moderating mechanism (known as "PD-1") of the Killer T-Cell found on the surface of the T-Cell. As I understand it, the normal purpose of this PD-1 mechanism is the downward moderation (or lessening) of the activity of the T-Cells to prevent them from excessive activity thereby damaging normal healthy tissue. By binding with PD-1 the Checkpoint stimulates it and this inhibits the Killer T-Cell from destroying the malignant cell. (See https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immune-checkpoint-inhibitor for more information.) This could be the way that some GBMs relapse after apparently reponding initially to DCVax. A small residuum of malignant cells which expressed a checkpoint epitope could escape the attentions of the Killer T-cells and so continue to regrow into a detectable tumour.

Such an outcome should be preventable by concurrent use of "Checkpoint Inhibitors". These include such medications as Keytruda which bind with and block the PD-1 on the T-cell thereby preventing the Checkpoint on the malignant cell binding with and activating it. This would otherwise inhibit the sensitised T-Cell from killing the malignant cell.

When Dr Liau said that "whilst this vaccine helps 20 to 50% of the gbm cases in this trial" she could have added (but didn't) the prediction that icluding 1 or more Checkpoint Inhibitors in the treatment regimen might significantly increase the number of cases responding to the vaccine. Trials to test this hypothesis are already under way.

Tryn, I have that feeling from what's been said by NWBO that they will want to maintain control over DCVax rather than let Big Pharma take it, if only to keep the price affordable for patients. This was one of the messages articulated in NWBO's presentation at the 2018 ASCO. You'll find it at 51.30 on this video

Logically speaking there should be no difference in the way any malignancy should respond to DCVax, either -L or -D. They all have the same pathological basis - that of a mutated and mutating genome which has allowed unfettered growth. The malignant mutations within the genome are expressed topically (ie on the cell surface) by proteins known as epitopes, each epitope being specific to an abnormal gene which has resulted from the malignant mutation. They are, therefore, not expressed on normal cells.

DCVax-L has been developed to act against any and all abnormal epitopes that it comes across in the manufacturing process. Not being expressed by the patient's healthy cells DCVax does not do anything to them, whereas malignant epitopes are recognised as "non-self" by the DCVax and attacked. Consequently, there is no logical reason to suppose that, for example, a rhabdomyosarcoma, a tumour of muscle cells, would not respond to DCVax just because it is a sarcoma, a tumour of a different embryological tissue (the mesoderm) to a carcinoma (the ectoderm). Irrespective of that origin they both express abnormal epitopes and so should be expected to be targeted by DCVax.

I can tell you that if I had a child with a rhabdo (and it is far commoner in childhood), I would plump for a course of DCVax before any cytotoxic or radiological therapy was allowed anywhere near him/her.

Hank, I have no doubt that you are correct. Faced with a patient who has a solid malignancy which is not responding to FDA-approved treatments, any doctor worth his/her salt, whether an ongologist or not, is going to suggest a treatment proven to be effective for a similar ailment even though it may be off-licence treatment for the patient's particular solid malignancy. With no danger of causing the patient any iatrogenic harm it's a "Heads, you win - tails, you don't lose" situation.

Word of mouth would soon spread that the treatment works without any ill-effects despite there having been no clinical trials for that particular form of malignancy making it increasingly difficult for any regulatory body to forbid its use off-licence.

Flipper, where does that assertion come from and what disadvantageous results are you implying might be coming our way?

Done.

I can understand that news of succeess in a trial could be delayed so that the successful company can indulge in a bit of grandstanding, but would a company without any good reason be allowed to delay telling the world about some "shocking" news such as the failure of a trial?

I hope that it is the speculation that is laid to rest and not DCVax-L.

WHY?????

So are opium and cocaine natural substances, so why would anybody with a single ounce of sense think that because high fructose corn syrup is natural that it cannot be harmful or addictive.

Answer: because Big Business will lie and dissemble to the public to promote its unhealthy product - just like not-so-Big Pharma used to do in the '50s and '60s and Big Tobacco has only just now stopped doing.

"There are lies, damn lies and statistics" (probably Mark Twain)

Guess into which category Sociopathleticism's analysis falls.

Maybe it perhaps, could be seen as being something like a semblance of a reasonable move if it delivers a fully functioning lab licenced to handle live biologics, a growing field in biotherapeutics

Sukus, it strikes me that for NWBO this could be something of a belt-&-braces strategy.

When the trial is shown to be successful then it's full steam ahead for production of DCVax-L and then Direct.

If, however, the trial fails then at least NWBO have not only their patents to sell but also a fully operational laboratory that should be able to handle any operation in the rapidly expanding field of Biotherapeutics / Live Biological Products (LBPs). Even if NWBO cannot run the facility itself a fully operational unit complete with staff should fetch a bob or two when sold to somebody who can.

Thanks, Senti (and all you others). It does..... and reassures me.

Flipper, you are doing yourself no favours. You very kindly provided me with details of the trial using a vaccine made from recurrent tumour and for that I thank you.
However, to react as you have done when I simply seek further information/clarification (provided by Biosectinvestor after your outburst) is both uncalled for and informative about you.
Despite that I wish you well.

Thanks, Flipper. The dendritic cell vaccine is "ATL-DC" ("autologous tumour lysate - dendritic cell") but I cannot see that it is DCVax-L or that NWBO is involved in the trial (even if it is only to say "ATL-DC courtesy of NWBO).

If this isn't DCVax, is it competition which might eclipse DCVax-L before its even got into its stride? I doubt that the study is going to last 10 years before results are through.

Flipper, I'm now a bit confused! Is NWBO conducting another trial of DCVax-L, only this time it is in patients with recurrent GBM who have not previously been treated immunologically?

That the DCVax-L in recurrent GBM is made from the original tumour is somewhat surprising to me. It is my understanding that it is highly likely that the genetic make-up of the recurrent tumour would have changed in the time since the initial biopsy was taken both because of the tumour's inherent genetic instability and the mutagenic effects of cytotoxic and radiological treatment.

In my naivety I have presumed that if an attempt was being made to treat a tumour immunologically, it would have been realised that after several months the genetic makeup of a tumour with an unstable genome (such as GBM), aggravated by radiotherapy and cytotoxic therapy, would likely be very different to that of the original biopsy. Thus, DCVax-L made from the original biopsy would be less likely to cut the mustard.

If it were my brain in which the GBM was advancing, I would seriously like the surgeon to go in again and if he did nothing else (such as debulking) he should take another biopsy from which to make DCVax-L for my treatment.

I'll second that, Smokey.