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Sojourner55,
Glad to be here. What a story to tell and be a part of. There is drama, intrigue, investigations and tension from the quiet wait. Behind it all are a group of small companies, some research hospitals and 2 Lindas with a passion for helping patients and hoping to bring a major change to the way cancer is treated and perhaps cured. Thanks for your part here too. Best wishes.
sentiment stocks,
So true. There is always a battle raging whether we see it or not. That's why we are commanded to beat our plowshares into (s)words until peace is established by a word. There is a Word that is sharper than any double edged sword and that word is truth. Long and strong. Best wishes.
iwasadiver,
What you just shared is exactly what I would have expected from Linda. I am patient because of my understanding of the science and because I was in a business that was cutting edge at one time and there is an incredible amount of "sod busting" to do. I challenge anyone to try to make a 200 sq. ft. garden out of prairie sod with 3 ft. deep roots using just a shovel. Then try 200 acres with a horse and plow. After that then maybe those who are impatient will understand better what NWBO is going through.
cannonblack,
Preclinical testing? No, that was done a long time ago. Best wishes.
TiltMyBrain,
It has to do with CXCR4. Best wishes.
iclight,
Progression was inevitable for most if not all patients unfortunately. This has everything to do with understanding immune response times and cycles to stimuli. The spacing of the treatments is critical because the immune response is targeted, controlled and balanced while educated DCs remain on site or in L's case, also in circulation, which is not very long in either case. This response is not designed to be overwhelming or unbalanced, as some immunotherapies have proven to be, which tends to cause serious adverse events. Spacing and multiple injection sites are variables that appear to be critical factors with DC therapies and probably two of the main reasons for the pleasant surprise response seen in open label info among others already thoroughly discussed.
Doktornolittle,
You are correct about Highwayman4life and my due diligence has been confirmed by Direct's MO and comments made by Dr. Prins and much earlier statements by NWBO and Dr. Liau and her understudies.
Here is another clue for those who want to dig deeper. There is an underlying, well conserved pathway that NWBO understands quite well. Best wishes.
chinatown1980,
I have no inside knowledge that NWBO will target 13 cancers for the Phase 2 Direct trial. What I do know from my due diligence is that up to 75%-80% (maybe more if improved upon as hoped) of all solid tumor cancers are susceptible to DCVax-Direct. I believe, if my math is correct, that 13 represents less than this percentage range.
flipper44,
I have not dug too deeply into ARGS MO either because quite a while ago I decided that a company with both an intratumoral and intradermal DC vaccine had the best chance to knock out cancer where it starts and provide the best surveillance for any escape if and when they might ever be used together. Dr. Subbiah said Direct would basically be a game changer. My due diligence tells me the same thing and has for quite a while especially as confirmation of MO was revealed through published findings from Phase 1.
I believe that smart CEOs are already looking at where they need to be focusing their $ and research efforts if Direct lives up to the higher end of the potential that some now realize exists. Thirteen cancer indications is an incredibly bold move that is not going unnoticed.
flipper44,
Before NWBO announced the type of needle they were using for Direct, I actually had drawn up a prototype of what I thought they should do for the injections. I have this in my notes somewhere. I was glad to see the thought processes alligned. The best place to start injections is near the tumor margins to facilitate DC migration. I still believe electroporation would be optimal but perhaps not necessary. NWBO does have an ONCS connection though.
flipper44,
Yes, that is it but.. for long term control sufficient time (length of treatment regimen)is required with properly activated DCs maintained on location (interval spacing of injections) to achieve immune memory of T-cells and B cells and complete eradication of the tumor. Without this, overpowering immunosuppression returns for most patients that did not have a sufficiently initial robust response.
austinmediainc,
What do you make of the COO resignation at ARGS? Was that because of a better offer elsewhere? I have not checked into this yet.
flipper44,
I believe you are on the right track and there are certain DCs (if I recall correctly) that can survive in a hypoxic environment longer than others and or can also secrete higher levels of cytokines to generate a stronger immune response from infiltrating lymphocytes and ancilaries while controlling immunosuppression better.
Sub Atomic master,
Yessiree!
chinatown1980,
First of all, anyone who has read my posts for any length of time knows I call it as I see it. Secondly, both you austinmediainc and now others think that I might be working for NWBO. As I have told austinmediainc and others, I have no affiliation, directly or indirectly, with NWBO, it's management, affiliates, employees of same or relatives or friends of relatives of same to the best of my knowledge. The fact that both you and austinmediainc as well as others have asked me this makes me chuckle and think that this is what being balanced is all about.
As to your question about ownership, let me just say that warrants take money to convert to voting shares. Right now that is money that NWBO does not have that much of. My understanding is that they will make the money they do have stretch as far as they can unless any given situation creates a need to dilute again to maintain control of the company. Most construction contracts require at least 50% down and milestone payments on the way to completion. I assume this is the case here as well. If you have proof of something different please advise. Best wishes.
flipper44,
Good catch. I messed up on my train of thought and didn't go back and proof read it right away. I took a call right after sending the post and saw your post after the call.
I am always thinking about the M2 macrophage influence on immunosuppression and that thought jumped in front of my point about Tregs here and I wrote it down without thinking through what I was writing. Thanks for pointing out the error.
flipper44,
TILs can include M2 macrophages and T regulator cells as well to varying degrees. These are immunosuppressive as is the hypoxic environment where many cancer stem cells are conserved. Unprimed DCs do not regulate M2 macrophages or Tregs well because they do not initiate a strong enough immune signaling response or one that is long enough to overcome it's weaker response to inflammatory signaling they initially responded to. They can not stay in this tumor environment for very long and also meet immunosuppressive resistance to at the tumor draining lymph nodes when they manage to migrate there with antigen presenting capacity. In total, this prevents a "highly educated" and motivated immune response even when educated TILs are present because critical targets are in a submerged position unless and until a sufficient immune inflammatory response is created.
austimediainc,
I don't like dilution but I do take it as a given until long term favorable funding can be found. This strategy keeps and has kept Linda in control. I saw this as her strategy long ago. The longer validation takes and or income from HE is held back by negotiations the more dilution will occur. As long as manufacturing capacity and automation continues to improve so that DCVax is ready to hit the ground running when validation occurs, I feel the greatest limiting factor is being dealt with and moving longer term value towards nearer term realization. I believe Mr. Woodford sees this as well.
chinatown1980,
The need to fund manufacturing infrastructure and expansion should be expected to be ongoing. Whether or not this means more dilution before major validation news depends on when validation takes place and whether or not a source of income is generated during ramp up and any additional trials or not. We are hoping that some of a certain infusion of $250,000,000 into immunotherapy research will find its way to help fund DCVax trials at UCLA or MD Anderson and or that a collaborative combination trial will be announced but these won't take care of day to day contractual obligations necessarily so.. we wait for validation with the understanding that if Mr. Woodford buys more on the open market towards a critical ownership point, at some point more dilution will be needed to accommodate it for Linda to maintain control. Hopefully this is all worked out beforehand amicably.
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.