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Not sure if already posted, but support for adjuvant RT with higher CD4/8.
http://www.ncbi.nlm.nih.gov/pubmed/23384671
"CD4/CD8 co-expression shows independent prognostic impact in resected non-small cell lung cancer patients treated with adjuvant radiotherapy."
Abstract
BACKGROUND:
Though traditionally regarded as immunosuppressive, radiotherapy may also stimulate immune cells and facilitate an anti-tumor immune response. We therefore aimed to explore the prognostic significance of immune cell markers in non-small cell lung cancer (NSCLC) patients treated with postoperative radiotherapy (PORT).
METHODS:
In addition to demographic and clinicopathological information, tumor tissue samples were collected and tissue microarrays (TMAs) were constructed from 55 patients with stage I-IIIA NSCLC who received PORT. Tumor and stromal expression of CD1a+, CD3+, CD4+, CD8+, CD20+, CD56+, CD68+, CD117+ and CD138+ cells, as well as M-CSF and CSF-1R, was assessed by immunohistochemistry.
RESULTS:
In univariate analysis, high co-expression of CD4+ and CD8+ T lymphocytes as well as high expression of CD1a+ dendritic cells in the tumor stroma correlated with improved disease-specific survival (DSS). In multivariate analysis patients with stromal ?CD4/?CD8 expression had a hazard ratio of 21.1 (CI95% 3.9-115.6, P<0.001) when compared to those with ?CD4/?CD8 expression.
CONCLUSIONS:
Stromal ?CD4/?CD8 expression was an independent negative prognostic factor for survival in NSCLC patients receiving PORT, indicating a highly detrimental prognosis.
You raise a good point.
In my example I saw the extraction of tumor material as a by-product of the debulking/resection surgery that would be taking place as SOC. So, minimal additional cost apart from storage and admin.
Image guided administration would be a completely separate procedure.
I'm not sure who would carry the costs in this instance, but I would assume NWBO for the latter and the hospital for the former (as part of SOC).
Peak Sales Revenue Projections.
All this talk of when revenue is obtained reminded me of this little projected revenue exercise I posted on YMB.
Here it is again for your amusement/comments...
There was an interview with Les (and since repeated) that they estimate charging $40k per year for a 3 year course. So, $120k for one treatment.
No mention of whether additional dosing past 3 years would cost more.
Just wanted to join the love-in and say thanks for sharing your research.
Your thorough (and borderline compulsive) investigations and considered assumptions are much appreciated.
I can completely understand the need to step away from it. I barely have time to read what you write, let alone research, compose and respond so thoughtfully.
(I've only just now read the post I'm responding to and already there are 3-4 more pages of new posts to read (of which, I tend only to scan for posters who's opinions I trust, such as yourself, so don't stay away to long ;) ))
It's difficult to say.
Depending on how much vaccine they make for each patient (how much tumor is available to lyse) they could have anything between 3-5+ years worth of treatments.
I can't remember if the protocol allows continued treatments after the schedule is complete (apart from progression) but since years' worth of vaccines are manufactured for both arms, any additional manufacturing would either have to come from those who have survived long enough to have exhausted their original supply and still have frozen tumor tissue to create it... or have progressed and have new tumor tissue.
You would hope it were the former, but you couldn't be sure unless you knew the individual patients' enrollment dates and how long their vaccine supply was going to last.
Cognate should have records of when the first batch was manufactured and how many individual treatments they made.
If a patient requires more, Cognate won't know whether they've progressed or not. But they could assume that if they required more at the end of their supply (following scheduled treatment protocol) that the patients have exceeded SOC for OS
Awesome news guys. These are brilliant results.
Extra detail in the call confirms this to a greater extent. Only 3 patients on full dosage.
Not one to count chickens before hatching, but I can't understand why we're not all millionaires yet ;)
It's been an interesting market response to what can only be described as positive news.
Massive volume on the day of PR (shorts covering?) then moderate to low last session.
It begs the question, what do they need to do to catch a break?
Anyone tracking the sum of all these parts must be scratching their heads as much as I am.
Anyway, in response to these last posts, some more reading re: extensive necrosis...
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770541/
(>95%) (95%-99%)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362430/
(>30%)
http://www.europeanurology.com/article/S0302-2838(09)01193-2/fulltext/tumour-necrosis-is-an-indicator-of-aggressive-biology-in-patients-with-urothelial-carcinoma-of-the-upper-urinary-tract-img-src-manager-uploads-europeanurology-com-eur-articles-s0302-2838-09-01193-2-assets-eulogo1-jpg-alt-eulogo1
(>10%)
So, a bit of a broad definition between them.
Another quote from the PR says a "high rate of tumor necrosis" - equally ambiguous.
I'm also not quite sure what they mean by "partial collapse" of the tumor mass.
The only time I've read or heard "collapse" in reference to tumors was about the individual cells themselves. Perhaps because the DCs are doing their job from the inside out (from the injection site, deep in the mass)?
Opaque descriptions aside, the news is good: There is a meaningful effect and it's measurable and attributable to the treatment.
I'm not seeing the downside, if i wasn't already in as deep as I'm comfortable with, I'd be adding.
Best of luck to all holders, but most of all to those who are or will be afflicted by this f-ing disease.
(I can only reply to this, not a subscriber.)
You too, flip. Everything's crossed.
For what it's worth. You can put me in the "read into the title" camp.
As previously mentioned, there would be no reason or expectation to put "systemic" into the title.
Doing so suggests that they have a point of view regarding Direct's effect on just that.
If that point of view was negative, would you not just leave it at 'antitumor effects'?
I read this as positive. Just not sure how positive.
It would be a shame to see you leave permanently, Flipper.
You're one of the more thoughtful posters here and many appreciate your contributions, I count myself among them.
"Rah rah sis boom bah!"
Some people seem a little too happy about this dilutive funding for my liking.
I'm with austin on this one, a little transparency on the reason would be nice.
You reading this, Les?
It couldn't wait till after ASCO?
So many posts here now, it's getting harder to wade through (sorry for compounding issues with this).
I recall reading/hearing that the trial enlargement option could only occur after the 2nd interim look.
Can anyone else confirm this?
The new PR gave F-stain the fair opportunity to retract.
This makes any libel case that much more robust.
He possibly thinks his 'clever' wording below suffices as retraction (albeit, phrased as an insult) but it won't hold up in court.
(deleted)
on second thoughts, don't worry.
Perhaps waiting for the reimbursement approval, a 1, 2 punch.
(edit: Sorry, didn't see DrChuck's post stating the same)
Not for his family...
F-stain bashing tweets have sunk to semantics:
Adam Feuerstein @adamfeuerstein
Larry Smith calls my recent $NWBO critique an "Attack Job." -> bit.ly/UCz9te I'll correct his errors later, taking kids skiing today
Details
14m
biorevolution @biorevolution
@adamfeuerstein did you ever correct his errors? Or are you pretty much giving up now that $NWBO got approval in Germany.
ViewConversation
Adam Feuerstein
@adamfeuerstein
. @biorevolution Germany didn’t approve DCVax. Reading comprehension is not your best skill. $NWBO
Does anyone with a twitter account want to advise F-stain to brush up on his reading comprehension?
from the PR:
Bashers are committed to bashing, but their position is untenable.
The only downside I can see from this release is that there will be difficulty in enrolling the P3 trial at German clinics. Because people will be willing to pay in order to ensure they're not getting placebo.
That is a great problem to have.
Fantastic news everyone. This is, indeed, a glowing endorsement.
Here's to many more positive announcements, this is just the beginning.
Since NWBO is my largest holding, it only seems fitting that a German word sums up my emotions regarding the short bashers:
Schadenfreude.
Just to repeat, for all the people who can't comprehend what an estimate is:
Fox, your theory is as good as any. Insofar as we really have no idea.
But it's plausible.
The "DMC" and "DSMB" are the same thing and can be used interchangeably.
NIH prefer to call them the DSMB but FDA like to refer to them as the DMC.
Both, however are referring to the same group of people.
Not sure if you can infer anything from their choice of using DSMB in this PR.
Perhaps that this info has not yet been through the FDA? But now we're really getting into tea leaf reading.
Much like how others have interpreted the PR - I read is it being as positive as can be, without actually stating a halt for efficacy.
- They were compelled by shareholders to ask the DMC for an update.
- The DMC hadn't completed their review of the data, but were happy to recommend a continue with the data at hand. i.e They are satisfied that there is no safety or futility risk (otherwise they would not have given the decision to continue).
- If there wasn't the possibility of an early halt for efficacy they would have simply said it was a continue (and nothing else, like the vast majority interim 'continue' decisions)
- The extra color added with their statement: "The DSMB's review of the efficacy data is still pending." was put in for a reason.
That reason, I believe, was to infer that efficacy data is encouraging enough to warrant further deliberation.
This was my thinking last week, when I asked if anyone had modeled the window for the 88th event.
Since enrollment will have escalated it should stand to reason the additional 22 events would occur more rapidly.
Do we know if NWBO have employed a steering committee?
staccani: "Possibly HF's selling to each other?"
I think you've probably hit the nail on the head, there.
Hmm, good catch. Maybe.... maybe.
I think that's probably enough conjecture for me today, but it is fun to think about.
I think there's validity in the theory that the DMC could be deliberating on how to respond to a statistically significant benefit seen in a subgroup.
This would be a discussion between the ethicist vs the scientists.
The scientists would be loathe to unblind a subsection of the trial which could, in turn, potentially under-power the remaining groups.
The ethicist would argue that keeping placebo patients (who are in that subgroup) from a safe, potentially life-extending treatment is unethical.
It really is a tough call, if the subgroup (probably mesenchymal, which tends to progress more aggressively) is taken out of the placebo arm, this could artificially extend PFS of the placebo group making it harder to eventually approve the treatment at the end of trial - If the margins are closer than we might hope.
Been waiting for the bash. Steady increase over the previous week or so on no news. Ripe for shorting at the first sign of weakness. Friday started, no announcement on monday, so it continued.
F-stain is a puppet. There are bigger forces at work here, he doesn't have enough sway to drop a stock 10% on over 10x 3 month volume.
I would so dearly love a pre market announcement to panic the shorts (as happened with PRAN)
Anyone modeled when 88 events will occur? Must be nearing.
Don't like the amount of new pumper ID's on the Yahoo board.
Whatever their agenda, I don't believe it's for long's benefit.
I relaxed a bit when I saw we were down today. Constant climbs seem to be unsustainable. It's healthy to have the odd pullback now and then.
Hmm. I think his homeopathy analogy in the SA piece does us more harm than good.
Which is unusual because normally homeopathy has no effect whatsoever...
Rene,
Typically, for these types of trials, PFS and OS is measured in months.
80% response rate means 80% of patients have responded in some measurable way to the treatment. In oncology that means tumor shrinkage (partial response) or tumor eradication (complete response).
Adverse Events (sometimes referred to as Adverse Effects or AE's) can be regarded as side-effects. In a double-blind placebo trial they are the events that have resulted in harm to the patients (from either arm, treatment or non-treatment related). This could mean fever, headaches, nausea etc.
SAEs are Serious Adverse Events. These have a significantly more harmful impact (potentially life threatening)
"Events" (without the 'adverse') mean something else in this trial, either tumor progression or death.
We haven't been given details on compassionate use. But payment would be expected. (Anyone else found detail on this?)
The size of their footprint at ASCO makes me (even) more confident.
The combined space with the booths puts them in Merck's league
You don't try and play with the big boys if you don't think you have goods.
It seems to me that they are anticipating a lot of attention, or at least, positioning themselves for it.
Plus right by the food court. That's bound to get some traffic.
I wouldn't want to speculate.
Regardless, it's a nice safety net to have the potentially longest surviving patients in the treatment arm come from those with, generally, the poorest prognosis (mesenchymal expression = more aggressive growth).
This helps us two-fold in the separation of the KM curves in the early stages.
We're effectively taking the patients that would ordinarily die first and shifting them to the end of the curve, if you like.
This could mean the DMC are comparing those who progressed first in the control arm (who most likely have the mesenchymal gene), with the group to first progress in the treatment arm (the ordinarily longer surviving proneural and proliferative expressers)
It may artificially skew the results to the treatment arm's advantage in the earlier stages, so the DMC will have to take that into account with any projections.
(or maybe we just get an early termination for efficacy...)
Would be interesting to know if the mesenchymal subtype is one of the P3's monitored subgroups (i.e. "chances to win"). If pre-defined in the trial design, FDA might be more likely to consider it as a potential subset for post hoc analysis approval (if necessary).
If only downloaded that darned pdf.....
True, so one could assume (if all visible tumors were injected in a metastatic cancer) that if the vaccine cleared them AND no other tumors appeared elsewhere in the body (which you would expect in such prolific cancers) that a systemic response has occurred.
They way I was reading people's interpretation here was clinicians would purposely leave some tumors untreated as an experiment.