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Yes, I remember that tweet. I uploaded a screen capture of another to the LA story but doubt it will see the light of day.
Tweet was: "keep going after this company....I am getting tired of making money shorting $NWBO!"
Later on bragging about money made on backs of longs....
Wa Wa Waaaa...........
"Preclinical animal data have demonstrated that these aDC can mobilize both local and systemic immune responses, and effectively clear both injected (local) and non-injected (distal) inoperable tumor lesions."
Data in a PR or on the poster or this fish gets fried.
Thanks, I did read it and I couldn't find any language that suggested to me that the threshold for being statistically significant is flexible for the surrogate data used to seek AA.
Pyr wrote
The problem with this theory is that the primary endpoint is the surrogate. This is not a trial with a primary endpoint that is based on clinical efficacy with some additional surrogate endpoints. In a trial such as that you could argue that a surrogate endpoint is predictive of clinical benefit AND if that surrogate data were statistically significant then maybe it could be used for AA while waiting for the clinical benefit (efficacy). That is not what we have here with -L. Additionally, the p-value required to make the data significant at 66 events is not p<0.05; it's much smaller. You don't get a pass on demonstrating that the data are reliable.
I'm trying to follow your theory on AA, but it makes absolutely no sense whatsoever. Are you saying that the data accumulated thus far can be used for AA approval and then the trial continues as a post-marketing/approval commitment? You also said this previosuly:
You forgot to mention the lecherous older male PIs that will flock around the young attractive graduate students and post docs presenting their research. Never been to a meeting that there weren't a few stunners and they always had the busiest posters in the lot.
So which balance sheet do you think Linda was really referring to when she commented on how good it looked...Lol
Being that DCVax-L trial has an adaptive character, it probably follows the adaptive design guidelines provided by the FDA. You can find those by searching for the following:
"fda guidance adaptive clinical trials"
I don't think I've heard anyone discussing these guidelines on this board so I thought I would share the information. If I missed a post then my apologies. If this comes off as condescending or talking down to anyone then my apologies, especially to you "Top 20".
Along those same lines there are very good peer reviewed articles out there (some from the FDA) that go into great detail on the structure of adaptive design trials and the logistics. Here is one of particular interest to me that lays out the firewalls between the different entities:
Adaptive design clinical trials and trial logistics models in CNS drug development?
Sue-Jane Wang a,?, H.M. James Hung b, Robert O'Neill a
And another:
Adaptive design methods in clinical trials – a review
Shein-Chung Chow*1 and Mark Chang2
There are others as well.
I found some contradictions in the literature regarding sample size adjustment. The contradictions are around the use of blinded vs unblinded data to make the changes to sample size if needed. I've found that generally the view is that unblinded is more accurate and if an independent organization is used (I viewed that as a CRO (ISAC) or DMC) then the type I error can be controlled.
Here are some excerpts from the papers:
An abstract was pointed out to me by another member that is a TPS abstract and contains results in the abstract and in the poster body. Going back to the meeting site and searching with TPS in the abstract field and results in the keywords field pulls up more abstracts that got through. I can only say that I think this is what the woman I spoke with from ASCO was referring to when she indicated that this year they were reminding the authors not to do this and the reviewers of the abstracts not to allow this without an exception.
Fox,
This isn't right for ASCO TPS posters:
I got the distinct feeling in the conversation with the ASCO representative that they were trying to crack down on the practice of presenting data when designated as a TPS abstract. The woman that I spoke with said they had strongly encouraged their reviewers to not even allow the mention that "data will be presented" in the published abstract. However, it obviously has slipped through in the past. And also, with such a large footprint at the conference NWBO might feel a little like flicking their nose up to the rules. Overall, I'm very pessimistic that we will have any indication on the 14th that their will be data in the poster unless they get an exception, which doesn't appear to have happened (no caret in number). I'm still hopeful that NWBO will at least put some data in the poster regardless of the policy. The abstract should at least give us a good idea what the bulk of the poster will pertain too. Be it mouse data, trial design or something else.
okay folks, here is the skinny.
I called ASCO and inquired regarding the TPS policy. Basically there will be no results or conclusions in the abstract releases on May 14th. That section is not allowed in TPS abstracts and they do go through a review process that should preclude that.
With regard to the caret..."that means some exception was made". Could be why the abstract I pulled allowed some results to be disclosed.
With regard to other TPS abstracts with data and no obvious exception noted; those represent the few presenters that break the policy. They do not have ASCO police checking and tearing down posters that are forbidden. The person I talked to said they beefed up their policy information on the website, "forbidden" verbage, to try and convey more clearly what they expect.
NWBO could present data in their poster on the trial, but it would go against the policy and wishes of those organizing the meeting.
Here is the only example I could find of a TPS abstract with results from last years meeting. I don't know why they are so special... The ^ in the abstract number denotes an exception to the conflict of interest policy. I don't think this has anything to do with the results being reported, but it was the only thing I noticed different.
Maybe someone else can find another example. I searched meeting library using the terms "interim" or "open" in the keywords field with "TPS" in the abstract number field.
I would interpret open to mean open label. Not open=still recruiting.
I thought I had posted already that I had found something in the past abstracts, but I don't see that post anywhere. I guess I never clicked submit. Anyway, thanks for the links. I found that when I searched using the keyword "interim" that I did indeed find trials that were still enrolling and that presented data beyond safety.
Thanks Fox. I was not aware of that rule and it makes the ambiguity I perceived in the title make sense. Now the wait to the 14th will be interesting.
Dok I appreciate your support. I believe everyone should feel free to put forth their opinions as long as they do it in a respectful way.
I thought I had been pretty low key with my opinions compared to a lot of folks on this board. I certainly haven't purposely talked down to anybody. I guess when a person is insecure, the opinions and viewpoints of others can be intimidating.
Anyway, I've been reading a lot to try and clear up some questions about the -L trial but haven't gotten the post together yet. I intended to put together a long Pyr-like post, but the personal and harsh criticism has kind of taken the drive out of me for now.
I'll try to post what I've got some time tomorrow and let the collective chew on it if they want.
"egoism"
and
"Yet here you are, not publishing in the NEJM, but attempting to talk down to people on a message board, who most likely have more money than you, and better, Top 20 degrees. Myself being one of them."
enough said....
Hi Fox,
I believe I have found a couple of abstracts that report data from ongoing trials. I need to look more closely at what they are actually reporting. I only asked the question because I wasn't sure that releasing data from a trial in progress was totally banned or not at ASCO. I've not been able to follow all of the posts about this amongst the different members and I was a little confused after reading the ASCO policies.
As for the question regarding what more could I want. I'm only asking the question because as you know, if you report something unexpected and very important (a systemic response) you damn well better have the goods to back it up. Otherwise, you come off as an amateur overstating the data. Prominent MDs and PhDs will take you down hard for that. I've seen it at poster sessions and it isn't pretty. It's even worse when it happens during the QA after a talk.
My opinion is that the title is ambiguous because the data to prove a systemic response (and it takes more than tumor regression) won't be presented. The surrogate data for a systemic response will be tumor regression.
To summarize: They can say systemic in the title because it isn't directly linked to the human data and they will have the mouse data to back it up. It's my opinion; It doesn't really matter. I just wanted to put it out there for others to consider and maybe add too it. You never know what you are missing until someone shows you. I thought maybe I was missing something.......
If I'm wrong I'll probably never hear the end of it and If I'm right I'll probably never hear anything of it.
I actually did think about who was presenting the data and what that meant. Of course I think there will be co-authors on the poster too. Maybe you're right and maybe lots of very clear data will be laid out and the mouse work will only be in passing. But I'm going to stand by my original prediction until proven wrong or right in a few weeks. I think the poster will start with mouse data in detail and finish with human data on tumor regression at the site of injection and if we are all very lucky there will be some data on regression in adjacent tumors or even remote tumors and maybe some IHC on biopsies. I seriously doubt there will be any data that will go beyond that to prove a systemic response.
Over the last couple of weeks I've bought back about 1/2 of what I sold. Therefore, I do hope I'm wrong and we get much better data than I expect. Either way, I think the data will lift the price, the magnitude of the lift is my only question.
I have no idea about the bulk of the data one way or the other. Didn't intend to suggest that I did. Could be mostly trial, could be mostly mouse, could be balanced. As far as the title goes, it's a bit ambiguous to me and I think if you want the attention of a lot of people at the conference you make it more clear.
Also, I still can't find a single example of an ongoing trial presenting patient data. I know there was some discussion of this on the board...LBA vs TIP vs something else. I'm just wondering if anyone is aware of an abstract presenting trial data while the trial is still running. Maybe they are over the PhI and working towards PhII. Don't know.
As time permits I've been going through the ASCO library of previous years meetings. What I'm looking for is an abstract that presents data from an ongoing trial. I've probably looked at 50 abstracts and haven't found one yet. I'm now searching under open label. Anybody come across an abstract that would model what is expected from Direct...ie data on a human trial that is ongoing?
OU, your point about I/II is well taken. Wondering if they can present the phI data if that stage is over. Would have though there would be an announcement if that were the case. still looking
Wow, that is a very strong statement. The mouse data is in fact not known. It has not been published and it has been vaguely talked about with no level of scientific detail. I could very easily see a poster that reports on the mouse study that very nicely lays out the justification for the human study and then some preliminary results from humans. Do those preliminary results unequivocally support a systemic response? I don't know and neither do you. Unlike this message board, scientists, MDs and regulatory bodies like the FDA require a higher level of proof that something in fact works than your declaration that it does. Even simply seeing tumor regression at adjacent or remote tumors is not enough to prove that you have a systemic response. It is highly highly suggestive, but you have to check all of the boxes and show a mechanism to be able to state it. That's just how it works in science. Look at the papers that have shown systemic response. Look at how they supported the claim.....
There are lots of mouse model studies reported at ASCO. You can search the previous years abstracts. I agree that the presenter is a good sign. I have no doubt whatsoever that their will be patient data in the poster. But the question is whether the patient data support a systemic effect claim or not. If you look at the Triozzi et al. paper you can get an idea of what kinds of experiments support such a claim. Other studies of systemic response like the recent one with the testes antigen NY-ESO-1 trial have other methods that support the claim.
I guess I'll add to the chorus of others that are encouraged and say that I too am encouraged by the title.
However, does anyone else think that the wording is a little funny? Specifically with regard to the "for intratumoral injection" part. I guess I'm wondering why if you are seeing a systemic response in humans that you don't just say it more plainly:
"Local and systemic antitumor effects in patient tumors injected with activated autologous dendritic cells in a phase I/II trial."
vs.
Local and systemic antitumor effects of activated autologous dendritic cells for intratumoral injection: A phase I/II trial.
I'm going to go out on a very unpopular limb here and say that the poster will report on the mouse study work with some data on the PI/II trial.
I'm hoping that I'm flat wrong on this...
Thanks for the reference. That makes a lot of sense to me since it isn't likely the spread of the cancer to other parts of the body that ultimately takes the life of a GBM patient. It seems a forgone conclusion that PFS is a surrogate endpoint, but probably a very good one. I think there was a post a while back quoting a person from a brain tumor organization/advocacy group? The person quoted had met with the FDA and discussed trial designs and proper endpoints. i beleive it was the view that the bar for approval was pretty low for effectiveness.
It seems to me that the primary endpoint in the -L trial is in fact a surrogate endpoint. I think that has been what both cheerleaders and detractors have been saying all along.
Question: Has any study validated PFS as a predictor of OS?
Hi Long,
Sorry but I hve to be brief here. I'm in the middle of something at work that I can't be away from for long (no pun intended). I'll try ot get back to you with a more elaborate response if needed later when I have more time.
Basically, cells differentiate into DCs from a progenitor cell (myeloid lineage). I'm thinking that other immune cells can differentiate into DCs but I would need to look into that. Therefore, DCs aren't multiplied exactly, but rather are the products of a progenitor cell that differentiates into the DC. This is where the leukopheresis comes in to provide the mo/mx cells for this purpose.
As for the BCG, my understanding of its use is simply as adjuvant (in vitro). Since the tumor lysate is likely comprised of only self antigens, their will be nothing to bind to the pattern recognition receptors (PRRs). Self antigens don't have pathogen-associated molecular patterns (PAMPS). The BCG should, although I don't know that for certain. lipopolysaccharide (LPS) is a more common PRR activator. I think the BCG is present in combination with IFN-gamma to activate an arm of the pathogen response in DCs that will lead to lots of MHC:antigen complexes on the surface and also the co-stimulatory molecules needed to produce TH1 and CTLs.
Sorry so brief without more specific references....
Thanks Long. I know my posts are heavy on the science, but that's where I feel like I can contribute the most. Being of scientific mind I like to understand the the fundamentals of a therapeutic approach. In that way when I hear something from the company in a news release, presentation or paper I can hopefully determine what impact the news might have and guess about what it might mean.
As far as your question, that is a tough one to answer. I think if you look at it from a perspective of what is being induced that creates immunity, then probably the most important thing in my mind is T-cell mediated immunity. That is a broad topic that involves T cells that directly kill target cells, cells that promote T cells that kill targets and cells that act to limit immune activation.
Going from that perspective then off the top of my head, IL-12 is extremely important because of the effects I already posted. To just add a little more to the IL-12 story, IL 12 is one of the necessary cytokines to drive a subset of T cells (CD4) to become TH1 cells. TH1 cells are important for the reasons I already posted and many more reasons I've not tried to elaborate on. Activated DCs also make IL-12 that can then stimulate (with IL-18) bystander cells to make IFN gamma. IFN gamma is absolutely critical for so many relevant functions. For some pathogens winning or losing the fight depends on a continuous presence of IL-12. Take it away and the mouse loses. Take it away and then add it back after the mouse declines but before death and the mouse wins. I don't know if winning against tumor cells requires a continuous presence of IL-12, I suspect it might since tumor cells produce so many inhibitory molecules.
Once a T cell finds its matching antigen it undergoes activation and it is critical that the cell proliferate. A properly activated T cell can divide two or three times in a 24 hour period and can go on doing so for several days. Thus, one activated T cell can give rise to 1000's of clones that are all specific to the same antigen. IL-2 (T-cell growth factor)is an important proliferation signal for T cells that the activated T cells themselves make, but so do TH1 cells and other cells. In some circumstances the IL-2 made by the TH1 cell can be very important (for example when a naive T cell finds a tumor cell with a MHC:antigen complex that matches its specificity). Take away IL-2 and the t cell dies.
Those are probably the two most important in my opinion. But other cytokines like IFN gamma and TGF alpha are also very important.
Thank you Hank for posting this very encouraging and important study information. I'm extremely encouraged by the findings that have been reported thus far in the AV0113 trial. From what I have been able to deduce, it appears the therapy is strikingly similar to DcVax-. The DCs are loaded with tumor antigen and exposed to IFN gamma and LPS (LPS serves the same purpose as BCG in DCVax; both are thought to be TLR-4 agonist). The study material you posted seems to go out of the way to make the point that their DCs produce IL-12 for a day and that the cells are utilized within 6 hours to ensure naive T cells are exposed to the DCs while still making IL-12. That's important because IL-12 induces the formation of TH1 (helper) cells and amplifies their activities. In fact, TH1 cells continue to respond to IL-12 long after differentiation, and sustained IL-12 is required for the control of some infections. TH1 promote activation of T-cells when interacting with antigen on weak co-stimulatory cells (like cancer cells that don't have much in the way of co-stimulatory molecules). IL-12 also activates natural killer cells.
Interestingly, IL-12 levels are very high in low adherent DCs produced by the DCVax-Direct method.
I think the bit about inflammation confused with PFS is important. Clearly, inflammation is a good thing and a I would take inflammation over having "no fuzzy MRIs" any day.
curious, when did you see the financing news? There is no time stamp and I found it by chance on the NWBO website. I thought it my coincide with the trend up...?
Hi Jswy17,
I have no problem with people that have an opposing viewpoint. I welcome it really. I don't think there is anything to be gained if everyone agrees and has the same thing to say. I know that my viewpoint isn't particularly popular. I know that LTT's view is even less so. But my viewpoint is based on what I know or at least think I know. I'm sure your view is derived the same way.
That said, it's certainly possible that Marnix Bosch and the other scientist working with him have come up with a strategy that works. I inquired a few posts ago about why Bosch is in Seattle while NWBO is in MD. Where is the research being conducted? Who is conducting the research? No answers came... Maybe the research phase is over completely. I hope not. I don't think there has been a single peer reviewed article to come out of NWBO in over a decade. That worries the crap out of me.
As to what proprietary knowledge NWBO has developed, well I doubt that they have discovered some new magic molecule that when dendritic cells are exposed to it somehow overcome all of the hurdles laid out by tumors. One reason I think this is because I've read through the patent for -L and Direct, and although there are some modifications, there isn't anything groundbreaking in them. There is no mystery molecule in the mix; just standard cytokines and adjuvants.
NWBO has probably done the most of any company ever in optimizing the process of preparing the DCs and stimulating them to take up antigen and produce co-stimulatory molecules. If any DC therapy can work at this point in our understanding of immunotherapy, it will be the one that NWBO is developing. Maybe in the end there isn't a need for a new mystery molecule or combinatorial therapy. I think your model-T before the Porsche comment is not far from what I am saying. I don't believe that NWBO will totally flop. I think they will show some efficacy. I just don't believe it will be earth shattering and send the share price to the moon. I mean it when I say I sincerely hope that I'm wrong. I am tempering my expectations based on what I know. Now if something were to come along, like...oh I don't know, maybe an actual peer reviewed article describing NWBO's Direct technology in animals that changed our understanding, then my expectations could change. Or even better, how about a hault for efficacy! wow, that would totally change the landscape and dogma on immunotherapy.
I've been very slowly adding back my position in NWBO. Not exactly something a doubter would do.
IMO, the German approval is based on a perfect safety record and some evidence that the treatment is efficacious. That's it...well that and NWBO successfully jumped through all of the hoops that the Germans laid out.
Remember IMUC? They also had astonishing data indicating their treatment was efficacious. We both know that the trial did not exactly hit it out of the park.
However, I haven't written off IMUC either and hold a very small position that I bought after it crashed and after hearing more on the results. The more on the results was that there was some indication that the trial did show a statistically significant increase in PFS and maybe later OS too.
Do you think those that receive treatment in Germany will not also be seeking other treatments? This could be a win for looking at results of combining DCVax with other therapies.
I think any response to self would be attenuated fairly quickly. I could be wrong, but I believe what NWBO is hoping to "show" the immune system, in the tumor lysate, are tumor specific antigens.
Cancer cells escape the immune system by reducing/eliminating the MHC:peptide complex on their surface. In other words they don't broadcast to the T cells that they are "abnormal". Also, antigens taken up by dendritic cells and other antigen presenting cells will present the antigen to T cells in the absence of B7 ligands. That's because there are no signals (pro-inflamatory) to stimulate those ligands to appear on the surface of dendritic cells. What you end up with is MHC:antigen complex on a DC and no or not enough B7 ligands. When a T cell with the appropriate matching receptor finds that DC, it tolerizes the T cell. More ways the tumor screws with your defenses....
Tumors secrete factors that create a physical barrier. Tumors attract Tregs that then secrete factors (cytokines) that shut down CTLs and Th1 cells. And/or the tumor cells themselves secrete the factors that shut down the CTLs and Th1 cells. Also, when you have antibodies to a tumor antigen (probably early on in the disease) they cluster on the surface of the cells (bound to the antigen) and induce endocytosis of the antibody:antigen complex. Inside the cells the complexes are broken down and degraded. No more antigen on the surface...
The important thing to keep in mind is that tumor cells do make tumor specific antigens. Mutated oncogenes or tumor suppresor genes, proteins that are expressed outside of their normal location of expression, aberrant post-translation modifications (the protein is modified after it's made), and of course in some cases oncoviral proteins like in HPV.
Personally, I think that NWBOs technology is better suited as a complimentary therapy to another immunotherapy that disrupts one or more of these strategies that cancer cells utilize to circumvent the immune system. But maybe highly activated dendritic cells with and MHC:tumor specific antigen complex and buckets of B7 ligand can get the immune system to respond. I just don't hold the strong conviction of some that it's going to cure a person outright. My hope is to see an increase in PFS and maybe in some cases an increase in OS. Then maybe the therapy can be combined with other strategies. But that's my opinion and other people think differently...
The only appropriate research to show the treatment works or doesn't work is a placebo controlled double blind clinical trial. The Germans don't know the results of the trial or anyone else for that matter (excluding the DMSB of course).
Hi LTT,
I am fairly pessimistic also. However, more antigens actually can make a big difference. The antigenic breadth of a vaccine has been formally shown to matter. Take the work towards an HSV-2 vaccine as an example. HSV-2 is not a tiny little virus with a few structural proteins and a few more assorted non-structural elements. People have tried and failed time and again to develop a subunit vaccine for this virus. But an attenuated virus with much greater antigenic breadth has shown complete protection in animal models (unlike the subunit vaccine). The difference has been largely attributed to the number of antigens available to the immune system.
Having said all of that, cancer is not a virus. Cancer survives in the body through a process of immunoediting that shapes the cancer cells into something that can go undetected and unchallenged. The question really is whether or not NWBO has circumvented the countermeasures deployed by cancer cells.
Companies that change the way they produce a biologic must go through an internal change control process. Does NWBO even have a QA/QC with a change control process in place? When you change something of any significance the FDA will request equivalency data that can include additional trials. This can happen pre- or post approval. The company I worked for made a vaccine. The way the downstream processing was being done for the final product changed quite a lot from the vaccine that went into patients in the trials. We had to show the same levels of purity and impurities. Same potency, same stability. We had to do animal studies and additional safety studies. There were numerous hoops to jump through and this was all during the BLA process. If you make a fundamental change to the drug you will be required to do more trials. For L and Direct the drug is dendritic cells. The process for making the dendritic cells outlined for Direct could be adapted to the L process and it makes a lot of sense that it would be. However, it will be through a change control process and whether or not it could be accomplished without the FDA requesting some trial data is questionable. In general, once you start trials you don't change the process unless you absolutely have too. Once you get approval, then you try to implement changes that improve yields, stability, potency etc.
yes...within minutes of open. I thought everyone had seen it. The link is:http://www.thestreet.com/story/12652571/1/when-is-a-warrant-not-a-warrant-when-northwest-bio-is-raising-money.html?puc=yahoo&cm_ven=YAHOO