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austinmediainc,
Low share price and painful dilution protection for Linda and friends until.. the right time when big news can be released. After that the complaints will mostly disappear or be labeled "sour grapes" by most. Best wishes.
ae kusterer,
Similar situation could certainly be at least part of what is happening with NWBO. Equivalency testing has been discussed here and elsewhere. Manufacturing approvals are always a big deal and attempting to get process changes during an ongoing trial is tricky.
Doktornolittle,
There are 2 main types of macrophage characteization. These are known as M1 and M2. M1 type macrophages enhance immune response while M2 macrophages help apply the brakes and are immunosuppressive. They carry the PD-1 markers that help shut down the helper and hunter T-cell responses. Cancer can respond to attack by calling in these types of immunosupressive macrophages (M2). Properly activated DCs can apparently control these M2s with cytokine signaling in at least the mesenchymal subtype. This is consistent with higher numbers of T-cells present before treatment begins due to more targets that mesenchymal subtype presents. This is also why treatment spacing improvements in L and Direct have and should offer some positive surprises in the open label trials and Phase 2 Direct trial. Checkpoint inhibitors will also help weaker immune responses from other (less mesenchymal) subtypes to continue to progress even as the genetic changes to these tumors after chemo/radiation make them more mesenchymal like at recurrence. Best wishes.
exwannabe,
Did you notice that the source you used did not quote the actual points of contention or timing of tweets and inuendo much other than the one that he apologized for as being technically correct but also not new as was declared to be. I am familiar with apologetics and this piece would fail miserably under close scrutiny by any well respected professor of such.
jondoeuk,
Why don't you ask Mr. Woodford about his investigation. Your moniker indicates you might live within shouting distance. Seems to me his is the one you should be asking about. Best wishes.
longfellow95,
The immunosuppressive impact of chemo/radiation is generally temporary but as NWBO came to realize, there are those who remain immunosuppressed after this treatment. These are being taken into account for this study. Every little bit of understanding that helps account for trial data improves the odds for better patient outcomes. We are part of this process even if only a small part. Best wishes.
longfellow95,
Those preexisting T-cells are already primed and targeted to antigens on the tumor cancer cells. The reasons are varied for why some patients have more or less of these pre existing primed T-cells in their system but what is known is that they have been down regulated or prevented from active engagement on cancer cells by an immunosupressive response by the cancer or tumor environment. By maintaining primed and proper chemo kine secretion active in the tumor environment and in circulation throughout the body (DCVax-L/D) cancer can be kept in check and potentially eradicated with longer term immune memory by T and B cells.
TC Trader,
Thanks for your studied input. These moves are the ones that can point to changing sentiment or implementation of existing plans by large holders. Best wishes.
flipper44,
Remember a long time ago when I said that mesenchymal subtype was more important to overall response than methylation over on SA? Your thought process here reflects why. I had read that DC treatments were seeing better response on mesenchymal and that methylation was not as important except in strengthening this response. We now know that immunogenicity is created by increased production of neo antigens which happens with mesenchymal genotype (original form) and mesenchymal phenotype (caused by mutation from chemo/radiation intervention). Type of response to treatment appears highly correlated to the degree that mesenchymal expression actually occurs in each tumor and creates the critical T-cell targets that Dr. Prins mentioned. The observed measurable immune response potential appears to remain at the 80%-85% level as NWBO has previously reported and some of these would need CIs to improve OS outcome as there would still be a less than ideal biomarker profile and TILs in changed phenotype until, as you say, the crossover helps to upload them and immunosupression is controlled.
TZOR,
It's tough being so far on the outside of all the excitement that you can't see in.
koman,
Someone posted that Allan Butler of Direct fame, may have received both L and Direct at one time or another. I am in this company for this very reason as research has shown that intradermal DC vaccine is more effective with Intratumoral administration as well. Do you know if this may have happened or have you heard anything similar?
koman,
You sound like someone who would really like to see a breakthrough here but are totally frustrated with the company leadership. We all have been frustrated to one degree or another along the NWBO way but I suggest you focus your energy on understanding the importance of CXCR4 and why this is important to NWBO and cancer pstients. Best wishes.
flipper44,
Now we just need to get the laws firmly in place to move the approval process along as fast as the discovery process is being speeded up. Keep hounding legislators to push for expedited process on path to approval.
The big bios have made about 40% of the correction necessary to reduce the shock from change. They are running out of time. Hillary gave them an excuse. Oncology focused companies that are not on the cutting edge of a breakthrough in their fields need to begin to refocus their efforts asap or they will struggle to survive.
iclight,
I didn't know you were in the room when Mr. Woodford apparently signed that NDA. Can you tell us what he doesn't know about that spending spree NWBO has been on while building up manufacturing capacity? Enquiring minds want to know. Best wishes.
flipper44,
Remember that 4th injection point they focused on? Sufficient activated DCs up to week 2+ but by week 8 things start to change. Activated DCs have migrated away or died by about 4weeks prior. That gives the PD-1 response a chance since M2s are no longer kept at bay. Keep the vaccinations at about 2 weeks and you maintain control with those cytokine signals. Best wishes.
Pyrrhonian,
Thanks for your response but 2 major differences of opinion here and they don't have anything to do with NWBO public relations issues which they definately need to address. This is all about the science which is what they are good at.
Method A and method B were not originally expected to show much of a distinction. When they began to notice that there did seem to be a distinction (probably analysis of similar patient characteristics and cancer type to different treatment and not just because of improved performance status of those later enrollees since Drs. Subbiah and Bosch are better researchers than that) they came to the conclusion that method B would be used exclusively in Phase 2. They have yet to correct that statement. I can think of several other reasons that could be behind the lack of mention of method A or B now and part of it, as a minimum, may have to do with presenting more favorable data for Phase 2 vs the entire Phase 1 group. By the way, they changed to better ECOG scores because patients were being delayed immediate access to treatments and eventing before the treatment ever had a chance to work. You need to keep in mind that you used 3 "if" equivalent suppositions to come to your conclusion on this point. Based on these suppositions you stated "So trying to draw a comparison between the two as equal groups would be inaccurate." Your "ifs" would be easily resolved by sound scientific practice which Dr. Subbiah and Bosch are paid well to do for good reason and that has nothing to do with public relations either.
As far as your guess as to method A vs method B activation, I can almost 100% tell you that this can not be the case based on expected biological activity. The type of activation you suggest will not in and of itself create the type of necrosis reported from Phase 1. Go back and look at other DC direct injection studies and you will not find this happening anywhere close to the extent found in this study. There is a different MO going on here and I have given hints as to what I believe that is and so has Dr. Prins. Again these hints have nothing to do with public relations.
I know you believe you gave a good rational for treating all A and then all B patients by group. Based on what I know combined with what I strongly suspect about Direct maturation,however, switching back and forth would not be a major chore or expense and I strongly suspect they did just this to match up patient cancer type and performance characteristics as best they could and not because of public relations.
On a final note, survival, while hoped for, was not to be expected in as many patients as originally hoped for mainly because of spacing, dosing level and duration of treatments but also because of the potential differences in effect between methods used. These issues will all be addressed in the Phase 2. I don't know if the public relations issues will be. Lol. Best wishes.
chinatown1980,
In all fairness, method A and method B in Direct showed a clear distinction. This evidence mark a clear and recognizable benefit and the MO is in accordance to what I expected biologically to happen. I had an outside hope that immune memory might have a chance with one or the other methods but the muted effect of inappropriate spacing and amount was too much to overcome in most patients. That is being corrected. The only doubts I have is about when we will have full validation from the scientific community at large. The PI Dr. Subbiah already commented on his longer term expectations for this treatment.
flipper44,
SPA? Yes, I believe they know enough about MO to do this and if endpoints are chosen correctly be done with conditional approval in months perhaps instead of years. We saw the potential of a fast acting immune response in mice and although this should take longer in humans, the results should still be relatively quick.
Poor Man,
The big boys already provided validation with their own DC research. Pyrrhonian gave us the proof with the graphs he put up trying to show DCs alone are usually not that effective at doing anything but provide an immune response and minimal survival benefit. DCVax-L is different in and of itself compared to other DCs, though, and the injection among and schedule are different than what has been used before. This is why the big boys want to play in the NWBO sandbox which in combo terms is theirs alone by patent pending.
chinatown1980,
Soon was modified by "hopefully" which indicates the timing may not be right yet for one or more of the parties involved. Did't you listen to what Dr. Prins said? As to the 2014 announcement about Direct, sometimes plans change when you are actually learning something valuable from your trial. You should understand that very well by now since you spent all weekend learning about every delay incurred by NWBO over the last 20 years. I hope you share all the good things you found out with us too like job postings for expanded facilities and updated photos of building expansion and any new related videos that come out. Best wishes.
sentiment stocks,
Thank you for the kind words. As for the kids, night time driving and games during the day worked pretty well. You are correct in assuming that I do not anger easily. I have never put anyone on ignore either and I try to read every post here because even if I don't agree with everything stated, the person making the statement is always worth the time and cosideration that our freedom of speech was intended to reaffirm as the intention of our creator.
As to the grapefruit juice link, that situation totally speaks to the importance of having good friends and family when going through this whole ordeal that is cancer. That break in the tension of the battle stations situation was priceless. Best wishes.
sentiment stocks,
The really funny part to me about all of this is that Pyrrhonian put up a chart a while back demonstrating that DC vaccine plus checkpoint inhibitors was better than either alone. He was trying to show that DCs by themselves are not all that effective. Now, do BMY or MRK want just any DC vaccine or one that is as close as any at being proven very effective in at least close to half of all patients and perhaps many more. Imagine if the right combo of surgery (tumor load reduction), chemo/radiation (leukopenia and damaged remaining cancer cells), antiviral vaccines (improved DC migration) , IL-2 blockers (Tregs down regulation during lymphocyte buildup prior to and during immune response from DC treatment) and or DC treatment (immune response upregulator) plus Temodar (alternating immune upregulation with down regulation of cancer cell repair) and or antibodies (down regulation of immune response suppressors PD-1/PD-L1) were to be given in the right sequence. That might lead to all patients living longer right? Perhaps you can explain this to Adam in terms of how grapefruit juice works so that these concepts no longer fail to make sense to him like they do with Direct. Then again, maybe we should ask him to look up the definition of "synergy" and report back. Best wishes.
Stillwell888,
No need to keep your fingers crossed because the confirmation is just a matter of time. Dr. Prins told us all how cures can be achieved by clearing the tumors. He said DC therapy plus antibody/antibodies can do this. NWBO understands how to control the tumor microenvironment and why that environment changes to being immune suppressed. They know that educated DCs can become depleted before full immune memory is achieved and or tumor mass/metasteses can be too much for a fixed injection schedule without the help of antibodies and or chemo to overcome. They know how to improve methylation in some cancer subtypes with chemo pretreatment. They know they must stop immune suppressing M2 macrophages from gaining control of tumor and metastatic environment and they have clearly seen this happen in the crossover in L, when synergies are utilized, and made the changes necessary to achieve this for their Phase 2 in Direct. What they need most now are approvals for fully automated manufacturing and rapidly expanding capacity.
flipper44,
I thought I remembered seeing the exact wording of the HE requirements that Rk had placed on a link in post #57556. The post I was thinking of from 3-22-2016 does not have the link I thought I remembered.
ae kusterer,
Leukopenia after chemo/radiation is desirable in most patients. The reason is that Tregs are depleted along with the others. Fresh start so to speak. In some patients, however, this leads to a permanent reduced white blood cell count. This is not good. Those whose cell counts recover also see Tregs recover at this point unless IL-2 levels are controlled. Thus selectivity with the use of an IL-2 blocker favors recovery of white blood cells without the Tregs. There is also evidence that antiviral vaccines given prior to DC vaccination improves DC migration. Lots of good data out there to give us hope that we are closer than ever to controlling cancer or eradicating it. Best wishes.
highwayman4life,
I thought I posted a thank you for your post before but it must not have been sent so THANK YOU.
flipper44,
I almost included HE reimbursement in my "what if" post but left it out because of Dr. Prins comment about ongoing patient accrual in the trial. RK confirmed that full enrollment is a precondition for HE reimbursement. Now as to the splitting of hairs about this, the Germans kind of technically consider HE data as part of the confirming trial data so.. Dr. Prins may have been covering the bases so to speak.
Talk about knowing how to capture King Kong lol. Negotiate with NWBO or go it alone with lost revenue opportunity weighing you down.
lattices,
Lots of warrants out there that may be stock now or.. Mr. Woodford found a financier.. or a certain foundation or individual may have decided to get involved.. or someone put a down payment on future negotiating rights. When good news starts to make the rounds the unexpected can suddenly happen because someone wants to be part of a history and or money making event. Best wishes.
flipper44,
B+ is correct. There is a subset of DCs that are sporadically produced in some patients that are more potent. These apparently became more potent by maturation process. Recreating this maturation step for all patients is the hope. Fountain of youth so to speak.
Multiple targets creates greater opportunity for systemic response as higher levels of circulating educated and memory immune cells will be present to hunt down their targets.
The 2 week interval is critical as the tumor microenvironment forces DCs to become circulatory like scouts looking for a target instead of generals managing the fight and the microenvironment with their own signaling. Once they leave the PD-1 response begins to prevent further benefit from intervention.
TZOR,
We all want more info and we want it yesterday. Please understand that I am in the same boat but the MO is obvious so we must wait. What is being looked at and probably debated is much too important to risk creating any more controversy of any sort. NWBO appears to be in complete stealth mode until a predetermined point is passed. This may be to prevent opportunities for negative spin on anything they might say. We know that news is coming indirectly
through trusted sources like Dr.Linda Liau and Dr. Prins. They also appear willing to respond to some trusted investors. What is reported by these investors is hearsay but then we either can trust what they report or try to connect with NWBO ourselves. I am pretty sure they will talk to investors they can positively identify who just want info.
olivier.libouban on YMB posted comment indicating p=.oo46 for mesenchymal response on the chart shown at 12:50 on the Dr. Prins video. Maybe someone can get a clear screen shot to post. Maybe this coupled with temporary screening hold and perhaps petition to use that spare Alpha spend now makes a little more sense to AVII? Maybe finish enrollment with all or at least representative population of mesenchymal for better analysis? We know this would be "screening" related as the temporary screening halt was explained to us. Best wishes.
iclight,
How can you be accruing patients while at the same time be listed as active not recruiting unless you are over accruing during a still blinded or quiet trial period? He did not say "waiting to accrue" patients. NWBO said that they would continue to actively pursue new trial sites in anticipation of commercialization. For this to happen in Germany patients must be enrolled at the hospitals to receive final approval. My understanding of HE is that once a patient does not qualify for the Phase 3 ie no longer screening, they can apply as an HE patient. These patients have their data treated like they are in an open label trial with their data used supplementaly for the approval process. NWBO can treat them on a compassionate use basis out of pocket and wait for reimbursement when that is finalized or a patient can pay for the treatment out of pocket.
There is some speculation that an equivalency analysis or other regulatory decision has been holding up some of the compassionate use patients from entering the process. Dr. Prins may be indicating that this is no longer the case at every treatment site by the choice of his wording or perhaps, as your say, they are still waiting for more patients to enter the blinded trial, perhaps in relationship to approval for subgroup analysis as several have mentioned and the NWBO disclaimer would possibly be aligned with.
flipper44 and Senti,
Notice that Dr. Prins does not even mention the better responses seen when chemo is used to up regulate methylation in some non responders that Dr. Linda Liau mentioned in her video. When you combine all of these synergistic effects wow! These methods must now be encouraged to become standard practice while we await formal validation. I think the regulators have known this for a while now and I believe their demand for a crossover was serendipitous for cancer patients.
Ready4bluesky,
Have you considered the timeline of Mr. Woodford's selling of his AZN stake with Dr. Prins mention of a partnership deal with BMY and MERCK? If the negotiations with BMY and MERCK were with all 4 parties but final agreements are principally between UCLA and said parties then a formal announcement by UCLA may be necessary for NWBO to announce anything. Dr. Prins may be acting in the interest of NWBO investors without having UCLA make a formal finalized announcement until all parties are agreed upon the timing of such an announcement. If Mr. Woodford's intentions are still in doubt and or there is other news expected soon, the formal announcement might be timed to coincide with that other news. Mr. Woodford's cash in hand may also be pointing to this.
iclight,
That is really strange. When I went to that site there was no image at the top as a header like I saw before with the picture you and flipper44 mentioned only a credit.
Stillwell888,
I believe you are on the right track with your thought process. DCVax-L requires tumor lysate so L as it exists now may not be suitable for a vaccine such as the one you suggested, however, a partially allogenic (created outside of self vaccine) based on cultured T-cells harvested after DCVax-L treatment might be cloned and banked as a way to begin the process of creating an allogenic activated T-cell/DC primed vaccine that targets all critcal targets found in any given patient and will also have the capacity to hunt down mutated neo antigens.
Shorty on the move. Someone who hasn't been wrong in 2 years appears to have made a quick U turn. Who is selling their shares today? I guess someone had to sell the pearl of great price so that some one else could buy it. Maybe its time to set those high ask prices folks. Official validation from big pharma means there is a new base support price in the works generally at $5 and higher. FDA validation puts it well... from a failure price to a new technology platform leader price. Should that day occur soon, longs and cancer patients will lift their glass filled with grapefruit juice to celebrate a great victory. In one hand the victory toast in the other some very, very burnt toast to be piled high as a monument to the one who gave us the supreme placebo toast to remember hubris and distortedly disingenuous prose by.
sentiment stocks,
I also said last year that L would probably be partnered but not Direct yet because Direct had not been tested at optimal dosing amount or spacing which is needed to control immunosuppressive macrophages which are recruited by cancer. I have stated my belief numerous times on SA that Direct can control a subset of macrophages (M2) that are immunosupressive. I pounded on this with Pyrrhonian and he finally conceded that there might be some hope for this to happen. I did not show him my proof because I generally won't do that unless someone wants to show me and everyone else that they do not know what they are talking about and or are deliberately trying to mislead and refuse to concede a point they have no proof to contest. I also wanted the researchers who have spent so much time working on this to give their presentations on their timeline. Besides, I like to use a hammer only when it's needed because time by itself often brings the truth home.
While I am here senti, was there a direct reference to DCVax-L with regard to the talks about colaboration or could this just be a colaboration agreement with UCLA?
I ask because I don't recall hearing NWBO mentioned and I had heard or read something about a colaboration with UCLA and someone earlier this year. Best wishes.
Cherry Tree1,
One blessed word says it all....
SYNERGY