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I do like the idea of injecting multiple tumors even if there is a good systemic response. As I mentioned some time ago, each tumor is founded by cells from a previous tumor. Once each tumor is established new mutations occur that can change the genetic make-up, including immune recognition sites. -- Foxhound
Question: Could Tylenol reduce effectiveness? Of course, it must be used as directed per the patient's physician's explicit directions.
I only ask this because Dr. Gorter uses hyperthermia in his practice in Cologne to help potentiate dendritic therapy.
I remember. You were right of course. I think enrollment ramped a little faster than expected.
I actually hope they use another 3 x 3 for multi-tumor escalation. That does not sound like me, does it? Maybe not so far apart as this last trial however.
(Aside: My understanding in the current trial is that once there is confirmation the first tumor is dead, they start injecting another tumor.)
Multiple Injections:
My optimism is that there are 500 lymph nodes in the body, and unless single tumor injection appears to be sufficient (one at a time) creating a complete systemic response, multiple injections in tumors that are far apart will involve more lymph nodes and possibly the spleen.
My only concern is that high tumor load + multiple injections could lead to a cytokine storm unless they increase slowly.
Kudos to Les Goldman. He called it in his conversation with Highwayman. He thought there would be a delay in the pps response. Bingo. Even better, the reason he anticipated a price spike was due to institutional and big pharma interest expressed in Direct at ASCO.
I think they are concerned about that. Notice Cramer did not speak to anything but technicals, but just like his last maneuver, this statement makes him appear neutral or slightly positive on NWBO, or at least removed from the whole matter. AF clearly took the hint not to mess it up this time. I think they are concerned, but they also may think a few more technical recommendations can at least keep CNBC and Cramer out of hot water. To me, it's still transparent arse coverage. On the other hand, maybe they'll stop trying to destroy NWBO.
Thanks Bio for all your efforts!
So that's why AF suddenly tweeted he loved NWBO (sarcastically or not, it was a safety signal), and also why he did not respond to the latest PR with an article/blog yet.
Same one. See post #13071.
I highly recommend Reefrad's post #13099. It is extremely informative. Thanks for the education.
Often tumors will show initial decrease in metabolism and only later show decrease in size. -- Reef
I can tell you that from all of the PRs regarding response, the terminology used is extremely favorable and meaningful. It is not as subjective as certain people are trying to portray it to be. There is no question that there is a good response to this platform. -- Reef
I hope they can move to accelerated (conditional) approval from phase 2 (OK, maybe even phase 1) without blinding any trials. It would be cruel in this patient population with this technique. For the placebo patients it would be like signing their death sentence. Moreover, the procedure is not without pain. Biopsies and even injections in hard to reach locations can be more than uncomfortable in some circumstances. To do this with a placebo would be cruel and unusual punishment.
Pyrr,
Here is that video. Red originally published it on this board. Start at 4:40 to see what I am talking about related to dead tumors remaining in the body (harmless) after immunotherapy.
http://www.nature.com/nature/outlook/cancer-immunotherapy/index.html#editorial
Dendreon sponsored the Nature video, but it does not appear to be Provenge, because it is for Ewing's sarcoma.
I am contacting certain media, but I am trying to get them interested in researching the company thoroughly. I do not quite have enough trial information to conduct a full out blitz on everyone and their Grandmother.
Bio, re: Direct, my contribution for the time being would be message #13050 (you can pick out info that is helpful). Moreover, you can use message #12176 to explain that immunotherapy builds and chemotherapy fades. I would also suggest that if you include the mouse study results, you explain disease and cures happen much faster in mice.
Had the 9 of 9 tumors been removed from the body for pathology analysis, I think they are at the point where they would exceed the findings in the Triozzi study (the tumor size would likely further decrease as a result of the surgical excision occurring after tumor death (or dying) and releasing otherwise trapped debris).
I'm just interrupting for a second. If you write it, I think the Bloomberg article alerts you where you get the biggest institutional hesitations. They are:
1. 'Even NWBO states that you cannot rely on the earlier DCVAX-L studies, and it all comes down to what happens in phase III; and moreover, the DMC efficacy decision is delayed, and no one knows why.'
2. Bloomberg also emphasizes the early DCVAX-Direct data are simply based upon case studies -- (which is not exactly the case because trend data is also emerging).
Those are the 2 main issues Bloomberg uses to explain relatively low investor response. There are a million responses to these concerns, but they all involve education and processing. In other words, bogging the intended viewer down with too much background will not work, and your position must address their concerns in the most persuasive yet bare bones manner possible.
Thanks Jim. I placed a few thoughts in the comment section following the article.
It will be interesting when legitimate institutions, many of whom are already invested in NWBO, finally decide to increase their holdings substantially. I see their current investments as run-up place holders. I think Larry's thoughts on upcoming price movement probably coincides with the answer.
It seems that in some (hopefully most) cases, the tumors are dying faster than they are shrinking (as fox alluded to). That's a lot of mass for the body to dispose of. It seems akin to other lengthy processes (setting and healing of a broken bone). Of course, this extended gradual process doesn't mean it's not working. In those it seems to be effective in, apparently it does so very well. -- Pyrr
Reefrad gave us some interesting professional information/insight regarding radiology advancements. I hope he continues to educate us on this subject.
You made the right decision with the knowledge everyone had at the time and the technology that was available.
Yes, if response rate is the measure, and you are looking at 13 of 20 after 3 injections and 9 of 9 after 4 injections, in an eventual group of 36, they are probably at or near statistical SS on that measure (with early response rates best measured by tumor cell death % and t-cell infiltration).
Since tumor shrinkage is a component as well in the trial design for phase I, adaptive design may or may not be required before phase 2a to modify what endpoints are used, depending upon whether the dead but enlarged tumors, a phenomenon in some of the patients, start to shrink from approximately weeks 12-32, versus whether their shrinkage is not always necessary and/or does not always occur even though there is complete tumor death (aka: success). In other words, do we need to change how we define success?
As you point out, regardless, the results thus far are a miracle. We just want to take these results and use the best objective criteria from the data to determine what components/endpoints will be used to judge statistical significance in phase 2a.
IMHO you are 100% correct on this matter. SEC docs and old press releases verified it. I remember this clearly because it was a riddle that provided a solution. It is one of the primary reasons I first realized this company was capable of patience, thinking outside the box, working closely with the FDA and honoring prior and current trial patients.
Linda answered a question we asked regarding trends for Direct. At the time, she stated it appeared that time from initial treatment was not a recognizable pattern for discerning tumor response. Not surprisingly, this changed over time. Other early patterns may be developing.
1. Trend One: 4 injections appears to be a positive tipping point for observable cell death.
2. Trend Two: 8+ weeks appears to be a positive tipping point for observable cell death.
3. Trend Three: Thus far, Lung Pancreatic and Colorectal appear to be early responders, although I suspect there are more types responding.
4. Trend Four: The best objective test for tumor response appears to be biopsy for the simple reason that a tumor full of t-cells sometimes grows, stays the same or shrinks while it is dying and full of t-cells and other immune components. From other research I read, my best guess is that less dense tumors shrink while high density tumors with high hyaluron barriers tend to remain stable or grow slightly (even though they are dying or dead) -- at least initially.
5. Trend Five: Tumor cell death % and/or T-cell infiltration appear to be the most accurate initial assessment we have for treatment effect.
6. Trend Six: Tumor response correlated with patient's feeling of well being. This has been overlooked by commentators, posters and the investment community at large. This trend should not be taken for granted. Patient well being can be used as a clinical endpoint. Patient well being in a terminal patient is probably the greatest gift you can give someone short of stopping their cancer.
7. Trend Seven: It appears tumor responses improves over time. No limit to this trend has appeared yet.
8. Trend Eight. While early, the best responders appear to be in the lowest dose group, but this may be explained by the fact that they are the most mature group. I suspect it is the latter.
The latter. It's hard to get into trials. So you usually need to try to get into more than one.
I need to qualify my related answer I just gave. It was in response to the question if 9 of 9 patients were enough for statistical significance (in a 36 patient trial) at this time. See message 13023.
Liau, Boynton and Bosch?
No, it is not. There are 36 patients in the first phase. There are 24 in the next phase. According to all the literature I read on dendritic therapy and immunotherapy in the past, the results should become stronger. There is enough evidence right now, if one has studied immunotherapy, for any large pharma to say….Uh-oh. There is enough for any inoperable patient to place this trial in their top 2 choices. There is enough for NWBO to continue manufacturing expansion. There is enough for investors to know it is more than promising. If these were the only patients in the trial, then there would be enough for SS, but the trial would be too small to utilize. You need a "moderate" sized single arm trial measured against historical data to make a determination that the results are "dramatic enough" for approval in an otherwise untreated population group with an imminent serious/terminal prognosis. There is much more to say, but that is the minimum. My position is they can get there on phase 1 plus early (aka: incomplete) phase 2 data without a blinded trial. Many post approval one arm confirmatory studies would then be required. (I'd reiterate, the FDA's speed to approval may even surprise me.)
Excellent piece theel.
Perhaps by giving each treatment a different name, even though it is the same biologic, I can drive the point home to would be investors.
Many companies use their drugs for different purposes and therefore give them different brand names. DCVAX-Direct, like no other treatment before it, covers a number of applications. All of a sudden you realize how large this company really is -- if it continues to show progress across multiple cancers. The following is an imagined list (DCVAX-Direct already appears to work in some), but if Direct proves itself against the cancers below, it might look something like this.
1. Breathe Easy vaccine for Lung cancer.
2. Recover Vaccine for Colorectal cancer.
3. Fightback Vaccine for Breast cancer.
4. Sweetlife Vaccine for Pancreatic cancer.
5. Reanimate Vaccine for Prostate Cancer.
6. Liveagain Vaccine for Liver and intrahepatic bile duct cancer.
7. Overcome Vaccine for Ovarian cancer.
8. Speakwell vaccine for Esoughageal Cancer.
9. The list goes on and on.
While my names leave much to be desired, my point is, this really is a very large company with a gigantic pipeline.
Spot on!
By September 1, 2014:
1. 36 DCVAX-Direct patients will have 4 or more injections each.
2. DCVAX-L Phase III trial may be near full enrollment.
3. UCLA DCVAX-L and adjuvant trial may collect final data.
Over 1,500 people die of cancer each day.
How many people do you think are dying of cancer this year that could use this treatment?
Well done.
4 injections in 8 Weeks. 9 of 9.
I think your position is very sound. I'm clearly expecting more from the FDA than in the past, but I think they are ready and willing to go there. I am really advocating a position -- not an investment strategy.
"Dramatic Enough" Results. That is the key Pyrr. IMHO. With a continuing stellar safety record of course.
Linda stated in a recent conference call, I forget which one, that DCVAX-Direct will benefit greatly from the German regulatory advances made with DCVAX-L; as well as manufacturing and distribution.
These people go home to die. That's it. The longer the FDA takes, the more people die. That's it.
There is a huge difference when there is no medical treatment available. That is what these expedited programs were created for. I agree with the methods you project they will use, just not the timeline. The FDA will also use priority review. I think this gets approved based upon the initial phase 2, and the remaining applications are readily approved through label extension with single arm post approval studies to validate the findings.
Expediting Availability of New Drugs for Patients with Serious Conditions
^^^Press Link Above^^^^
Note, while the link site above addresses a specific form of cancer, the webcast in the link addresses all types of cancer.
"Dramatic enough" results can lead to approval for treatment even from a modest sized phase I study in a serious disease with only a single arm study held up against a historical control. (Start slightly before the 54 minute mark through 55 minutes 23 seconds.)
If you look at the timing for approval on recent cancer drugs, they've been getting approved in "4 months much less 6." (Start at 45 minutes 58 seconds.)
Robert J. Temple
Deputy Center Director for Clinical Science
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
DMD Webinar
February 20, 2013
Hi Ou,
One thing I was wondering about was that there was no mention of a systemic response. Will they need to inject every tumor? Can't there be a lot of them in one patient? How would that affect the cost of the treatments? -- Ou
Funny you should mention that. I contacted 5 major media conglomerates today. I think they will be glad they started researching this story now, because they need a fair amount of time to do background research. Linda Liau, her UCLA peers, Bosch, Bonynton, Linda Powers, patients, critics, dendritic science, etc. I am looking forward to Ken Burn's special next spring. If he starts following NWBO now, I think it will be his crowning achievement. Patients everywhere rejoice!
Upgrades around the corner?
Flashback.
….I can foresee Direct being approved in the 15 - 30 month window. Those inoperable patients need help, and the FDA wants to help them. I think the speed could even surprise me. May 30, 2014
Congratulations NWBO!