Replies to post #81344 on NorthWest Biotherapeutics Inc (NWBO)

[chinatown1980]

That's depressing. Here's another question if you would oblige. UCLA has been able to consistently achieve longer OS with their use of DC vaccine over standard care. Do you agree? If so, which of the following do you attribute as the reasons why the Phase 3 will not replicate what UCLA is able to accomplish?

1. Surgery procedures and techniques at UCLa are superior to the hospitals in the trial.

2. Vaccine in trial not manufactured consistent with UCLA'S

3. Vaccine in trial is an older version of the technology that UCLA is currently using.

4. Other factors, like patient characteristics, skew the results at UCLA vs. the general population in trial.

5. Other

[RuleofK]

AVII77
Would you mind explaining what MST and "average survival" are, and why the latter is meaningless? Also, are the OS data recorded at the time of death regardless of the cause of death?

[PacificNW]

So let me get this straight, AVI proves that the trial is absolutely flawed and that NWBO could have intentionally misinterpreted the numbers to show DCVAX extending life when it really didn't. I mean this can't be a coincidence, it absolutely benefits NWBO to show DCVAx extending lives, so if it really isn't extending lives as NWBO showed in their proof diagram then NWBO only erred on the side of life extension which only benefits them thus making it intentional in AVI's opinion, that is what he is stating and he supply's his proof. A company cannot make such a flagrant error and call it an oops. They are entrusted in setting up the trial and interpreting it, period, no excuses here, especially one that could have changed the course of history and course of a patient's life.
So now the question begs is AVI really correct, does he know more than the researchers at NWBO and
can his interpretation stand since I don't know squat and was trusting NWBO and the Doctors running the show.
I guess this will be a defining moment for all of us, scary that AVI has presented this proof of work.

[Rkmatters]

The Abstract says:
"A second cohort of patients with rGBM consisted of 8 patients with recurrence following several adjuvant temozolomide treatment cycles. Median OS for these patients is 14.7 months from the time of surgery for first recurrence. The comparator for this cohort is derived from Friedman et al. (2009), who reported mOS of 8.7-9.3 months from the time of first recurrence for rGBM patients treated with Bevacizumab with or without Irinotecan"

There are two errors here.

1. The Median OS for these patients was NOT 14.7 months it was 11 months. -- AVII

The error is on your part. I imagined you were not using a chart that had final events for patients. But then I found this.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018463/

Here is what they had to state about the OS for those 8 patients elsewhere:

For recurrent patients that enrolled in our vaccine trial (n=8), the median overall survival was 17.9 months from the time of initial glioblastoma diagnosis. OS was significantly longer for those who received DC vaccination at initial diagnosis compared to those who enrolled in this trial at the time of recurrence (p=0.03; Supplementary. Fig. 2).

and here:

While the number of glioblastoma patients entered in this Phase I clinical trial was not powered to measure efficacy, the clinical results of this trial are still noteworthy. The median OS from the time of initial surgical diagnosis was 31.4 months for all glioblastoma patients (n=23) treated in this study, including both those enrolled as newly diagnosed and recurrent tumor patients. For those treated in the newly diagnosed setting, the OS was 35.9 months; and the OS was 17.9 months for those who received vaccination at recurrence.

And so, the data in the abstract points out that they enrolled patients who were rapid progression patient. From the 17.9 OS, those patients were enrolled essentially 3.2 months in. True Rapid Progression patients are not chemotherapy responsive. They have the enzyme to correct the damage that chemotherapy does to DNA, and thus not responsive to cytotoxic drug. Rapid progression patients are mostly unmethylated MGMT promoter tumors.

O6-Methylguanine DNA MGMT Promoter

The methylation status of the MGMT promoter has been shown to be a potent prognostic factor in patients with GBM; cells that are deficient in MGMT have shown an increased sensitivity to TMZ. Patients with low MGMT expression (due to methylation of the promoter) benefit more from adjuvant TMZ. Furthermore, patients with methylated MGMT show pseudoprogression more frequently. Until recently, it was not well established whether this latter finding was due to frequent tumor progression immediately after treatment in unmethylated MGMT and, thus, unresponsive tumors or due to a high incidence pseudoprogression as a consequence of higher sensitivity to treatment; we now know it is the latter. MGMT promoter status may predict pseudoprogression in >90% of patients with methylated glioblastoma. An approximately 60% probability of early true tumor progression was observed in unmethylated MGMT promoter tumors.11

The abstract median for the 8-patient is as stated:

Median OS for these patients is 14.7 months from the time of surgery for first recurrence.

The abstract conclusion is real. It is not imagined.

The Abstract conclusion says:
"These results suggest that treatment with DCVax-L can extend survival by 5 months or more in patients with rGBM."

You continue to review the data presented out of the proper context it is put in. And then you run off and make incorrect conclusion. I don't even need to look at your conclusion for the comparison, as I automatically know yours is wrong.

The fact that you continue to accuse reputable investigators of improper conduct after repeatedly being shown you are wrong to me shows how you're not interested in the truth. It also shows your lack of comprehension of the neuro-oncology topic. How you discount and mock 14.7 months extension in survival for rapid progression patients is beyond me. But, we all have our own hobbies.

[biosectinvestor]

A few thoughts here, let me first say this is a brief reply, because I don't claim to have the time to decompact this post, but I find some items interesting.


1. I'm not sure why you did not include the abstract. It was easy to find here: http://www.ejcancer.com/article/S0959-8049(15)00060-X/abstract?cc=y=

2. It's cross-posted at iVillage: http://www.investorvillage.com/smbd.asp?mb=6543&mn=6379&pt=msg&mid=16510416

3. As a quick addition, to my comments below, I note that the article is discussed here as well, but in a more dated, discussion that suggests it is not in the context of pending release of data. I think it's worth reviewing this discussion, though I don't have time to delve into it, I think it's a more positive take on the details here: http://www.siliconinvestor.com/readmsgs.aspx?subjectid=56756&msgnum=633&batchsize=10&batchtype=Next

And I'm not sure that anyone who can rebut it will post on both sites. But I would be interested to hear more. I think it's flawed to rebut to an abstract. It's also unfortunate if you don't list which article it actually is and who the authors are, while accusing them of some quite serious either failure in their expertise or fraud.

It seems to me that your quote of the conclusion is not exact, because the conclusion refers to TWO cohorts and you wish to focus only on these 8 patients, out of context:

Results and conclusion
The results obtained in two cohorts of patients with rGBM suggest that treatment with autologous DC pulsed with autologous tumour cell lysate can extend survival by 5 months or more.

http://www.ejcancer.com/article/S0959-8049(15)00060-X/abstract?cc=y=
https://www.researchgate.net/publication/276494898_ITOC2_-_017_Prolonged_survival_for_patients_with_recurrent_glioblastoma_multiforme_who_are_treated_with_tumour_lysate-pulsed_autologous_dendritic_cells

ITOC2 – 017. Prolonged survival for patients with recurrent glioblastoma multiforme who are treated with tumour lysate-pulsed autologous dendritic cells

Bosch L. Marnix, Prins M. Robert, Liau Linda

As a check on the view of other scholars on this article, one might check if it gets citations by other scholars.

Here are more resources:

From NWBIO website: http://www.nwbio.com/AACR_poster_prolonged_survival.pdf
The above linked pdf includes lots more data than you have in your analysis of the abstract, including additional charts and other information. As I said, I'm far too busy today and in the coming days to probably dig into this but, I'd suggest it is well worth further analysis. But it's kind of basic courtesy to include the links so others can evaluate what you're saying and if it is solid or based upon a misunderstanding, etc. Just a request that you please include the link when you post and cross post it so that people can fairly review and analyze what it is that you're saying.

'AVII77' Quote:
If you know something about these 8, please post it.


The Abstract says:
"A second cohort of patients with rGBM consisted of 8 patients with recurrence following several adjuvant temozolomide treatment cycles. Median OS for these patients is 14.7 months from the time of surgery for first recurrence. The comparator for this cohort is derived from Friedman et al. (2009), who reported mOS of 8.7-9.3 months from the time of first recurrence for rGBM patients treated with Bevacizumab with or without Irinotecan"

There are two errors here.

1. The Median OS for these patients was NOT 14.7 months it was 11 months.

2. Their comparator, Friedman 2009, did not report "from the time of first recurrence for rGBM". They reported from the time of randomization (a later timepoint than DCVax's "from the time of surgery". Freidman: "The median OS times from the time of random assignment were 9.2 months for the BV group and 8.7 months for the BV + CPT-11 group"



The Abstract conclusion says:
"These results suggest that treatment with DCVax-L can extend survival by 5 months or more in patients with rGBM."

And it should say:
"These results suggest that treatment with DCVax-L can extend survival by zero months in patients with rGBM"

But the good news for longs is that they don't have to worry about cross-over confounding the ITT OS analysis because this data suggests that DCVax doesn't do Jack in that population.

I wonder if that will make it into MD1225's upcoming SA article.

These people have, IMO, no business running a clinical trial in human subjects until they can:
1. Correctly design a trial,
2. Correctly assess the results of the trial,
3. Correctly interpret those results, and
4. Correctly report those results.

(Good luck responding to that w/o violating the TOS)

Finally, we have all lost loved ones to cancer. And we will lose more. It turns my stomach to think of the hundreds of millions of dollars that went into this program. And don't kid yourself, that money was diverted from other projects; as a society we only have so much to spend. The Woodford's of this world do not have bottomless pockets. The cure that could save your child could be sitting on a shelf somewhere waiting for the funds to bring it forward.