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Here is a very thoughtful post by Larry Smith in the comment section under his latest article. It is a response to AF.
Your reliance on the RECIST criteria and the observations you have drawn from it are consistent with what we would expect from chemotherapy or targeted therapy. If there is to be an effect of the drug, we should see a fairly quick shrinkage of the tumor. However, this may not be appropriate for immunotherapy.
The hypothesis behind immunotherapy is that we can enhance the activity of both the innate and adaptive immune systems to attack the cancer cells. It is the role of the immune system to eradicate abnormal tissue as in cancer. However, when cancer occurs it is because the immune system is neutralized or too weak to be effective. By bolstering the immune response, the hope is that we can have a meaningful effect on the cancer and hopefully eradicate or slow its progression.
What has been demonstrated so far with the two approved immunotherapies Yervoy and Provenge and experimental treatments like nivolimumab and lambrolizumab is what appears to be a paradoxical effect on the tumor in which the tumor size may actually increase in the early stages of treatment. The reason is that if the therapy is working immune cells infiltrate the tumor mass and the resultant inflammatory process actually increases the size of the tumor. Ultimately, we should see a lessening or ending of the inflammatory process. Also, macrophages should eradicate the necrosed tissue and the combination of these effects should manifest in tumor shrinkage.
The hypothesis for the mode of action for immunotherapies is that they bolster the inherent immune response and that this is manifested by infiltration of immune cells into the tumor that leads to necrosis of tumor tissue. The biopsies taken of tumors that respond to DCVax Direct do show tumor cell necrosis and immune cell infiltration in patients who respond. Through imaging, we are also seeing shrinkage of the tumor in some patients.
All of this is consistent with what we would expect from an effective immunotherapy. Based on the experience with the prior drugs that I mentioned, we would expect over time to see further shrinkage of the tumor.
I also think that you should consider that these are heavily pre-treated cancers that are inoperable. This is not like treating a slower growing cancer. It may be the case that the best we can hope for is stable disease or slowing the progression with acceptable quality of life. The benign side effect profile of DCVax Direct would encourage its use in these aggressive tumors even if it did not shrink the tumor.
We are seeing a very interesting biological effect that is consistent with the use of autologous dendritic cells to augment the activity of the immune system. This is quite encouraging. It is too early to claim that this is a paradigm changing means of treating cancer, but it is certainly inappropriate to rigidly apply the RECIST criteria and conclude that there is no drug effect.
In the 5 responder patients, [an average] 6.8 vaccinations were necessary to induce an objective clinical response. bloodjournal.org/content/102/7/2338?variant=short
Think about cost and licensing.
NWBO would be broke right now if it had been leading these 2 trials during this time.
UCLA would never speak like this if it wasn't planning on a licensing agreement with NWBO.
Quote:
The Jonsson Comprehensive Cancer Center at University of California, Los Angeles, is conducting this phase II trial for newly diagnosed or recurrent anaplastic gliomas or glioblastoma. Eligible patients must have surgery performed at UCLA to obtain tumor tissue to create the vaccine. The patient's own dendritic cells are pulsed with tumor lysate (from the patient's tumor tissue). The dendritic cells are then reinjected back into the patient, training the immune system to recognize patient-specific tumor antigens. This is the same method used in the DCVax trials. The current trial is randomizing patients to three arms: arm 1 receives the tumor-lysate pulsed dendritic cell vaccine plus placebo cream or saline injection; arm 2 receives vaccine plus resiquimod cream (an immune activator); and arm 3 receives vaccine plus intramuscular injection of Poly ICLC (another immune activator). Estimated enrollment in this trial is 60 patients, and estimated primary completion date is September 2014. NCT01204684
See also:
http://clinicaltrials.gov/show/NCT01204684
The Street's written version v. Cramer's actual wording seems highly calculated. Cramer can fall back on either interpretation.
Exactly,
The last one we know about, if I remember correctly, probably was the OK to go forward with the Direct Trial.
So….maybe I can't speculate on a (potential) more current validation going on behind the scenes with AA initial review by the FDA, but what I can say is that LP would not say "validation NWBO continues to achieve from regulators in both the U.S. and Europe…." if there was something negative from the FDA coming down the pike.
Encouraging.
"Feuerstein’s “analyses” are contradicted by the concrete data from world renowned cancer centers, and by the validations NW Bio continues to achieve from regulators in both the US and Europe, key opinion leaders, healthcare system institutions, grant agencies and others." -- NWBO
I think immediately of "Hospital Reimbursement" in Germany, but I think it goes beyond that. US insurance coverage for new Expanded Access, perhaps? -- Pyrr
I should add one more thing that just dawned on me. The release of information on DCVAX-Direct yesterday by Linda, and in PRs on May 15 and 27 prove that the DCVAX platform works on more than just GBM.
What I said may sound really obvious, but look at what a grand introduction this is for upcoming phase III DCVAX-L results if they go well! It would likely sound something like this:
"The results we received for DCVAX-L are very gratifying indeed, and we expect it to be a co-primary therapy in the S.O.C. for GBM, oh and by the way, the very same platform ingredient is now known to work in multiple diverse cancers, and consequently we anticipate working with the FDA and clinicians to get DCVAX-L to all solid tumor cancer patients as soon as humanly possible."
Reporter Question: Do you see physicians using DCVAX-L immediately off-label for other cancers after it is approved for GBM?
NWBO: Those are decisions between doctor and patient. I cannot speculate upon potential off label use demand at this time:)
An additional upside to very early Direct results?
I want a cure to cancer as much as anyone else. Still, as OU stated some time ago, let's lower the bar a little. We are getting much closer. We will get there, but let's appreciate the current progress.
The amazing initial results after approximately only 3 injections over the course of 14 days are, as Reefrad put it, "spectacular!" It's amazing we even received results at all by the time ASCO came. Did anybody think about the very precise timing with which these young results arrived. We started last June, ASCO was probably booked very early 2014. The timing into ASCO was so perfect that it appropriately wetted our whistle, but it also makes us realize the Direct timeline ahead. As L.S. stated, we are looking at March 2015 to start phase II. This is still very near term for such a promising drug, and if a concurrent phase 2b initiates at the same time (blinded), we can expect an ethics review board would be pounding the table to unblind the trial very quickly into the trial -- very quickly indeed.
So what is the additional upside? DCVAX-L has a massive infrastructure built up in the United States and Europe. Further expansion is just around the corner. Many months ago I was stating that DCVAX-Direct could one day overshadow L. That same conclusion was likely independently reached by many players needed for DCVAX-L to succeed. Notice the schedule for DCVAX-Direct vaccination. Day 0, Day 7 and Day 14, followed by injections at Week 8, Week 16 and Week 32.
Now imagine if ASCO came when we were at Week 8 or 16. I can almost guarantee you that the results would be both quantitatively and qualitatively far beyond spectacular. I base this upon the Triozzi study which used a less potent version of Direct like therapy on about 8 patients. Many patients in the Direct trial had not even reached the point at which Triozzi removed the tumors to evaluate them. Remember? After excision, the tumors disintegrated by oozing clear liquid.
Again, keep the L infrastructure in your head. Right now, everyones' whistle is wetted to the spectacular Direct results, but immediate expectations for almost instantaneous success are chastened by the clock, and by the realization that phase I results need time to mature. Now L can shine if the phase III results come in with statistically significant results for approximately 6 month PFS improvement (4 months would likely do it). Remember? No serious side effects. Direct can then go upon the hard work of proving itself over time while L takes its rightful place as the post-surgical post-radiation standard of care (in addition to Temador (initially)).
Waiting in the wings are UCLA phase 2 studies on two additional updated DCVAX-L like vaccines using different maturation agents. These should be reaching full enrollment any day. They are also likely using the more potent DCVAX-Direct manufacturing techniques. So you can see the timing, if things go well, places those latter patent pending(?) improvements on DCVAX-L Advanced in parallel timeline development with DCVAX-Direct.
Meanwhile, Original DCVAX-L will have at least 2 years to dominate and set the stage for these three other players. Thus making any concerns regarding overshadowing obsolete.
That last paragraph from today's P.R., before the obligatory paragraphs.
“Feuerstein’s so-called “analyses” consist of false statements, serious misrepresentations and personal attacks and smears,” commented Linda Powers, CEO of NW Bio. “Feuerstein’s “analyses” are contradicted by the concrete data from world renowned cancer centers, and by the validations NW Bio continues to achieve from regulators in both the US and Europe…."
Much of what was in that article was also diligently independently arrived at by Reefrad, Pyrr and host of other board members putting their heads together.
I applaud NWBO's immediate, strong yet measured response to AF's false claims.
Fox, have you read or heard anything yet regarding DCVAX-Direct dendritic cell migration from the tumor to the lymph nodes?
Sitiain, I like the way you are going about things. Mother Teresa once said, don't have a March against war, have a March for Peace. (I'm not particularly religious, but it's a great reflection)
With all due respect to a Saint who did more good than I could in 100 lives, I think one has to do both.
If and when we get some idea regarding DCVAX-L's progress, I am going to work on the march for peace side first.
Any fool (I'm referring to my alternative self here) could try to saturate the retail investment community with manic predictions regarding a company they invest in. In other words, while the hedge funds are illegitimately bringing NWBO down, the longs probably should guard against recommending a stock to less diligent investors around the world until said Longs confirm the chances for approval and success are astronomically high.
BioInfo, if he's not bluffing, hired a lawyer to go after AF via the FBI and SEC. Of course, one must trust those agencies also are not too far gone. In other words, BioInfo is marching against naked short sellers. I also applaud this tactic.
I'm in waiting mode, but I am beginning to compile an unprecedented list of appropriate organizations and people around the world we can all write letters to in order to create a groundswell of investor support. That day has not come yet, because the current phase III critical data and regulatory position are awaiting release. I hope this does not remain a "battleground" stock for AF. I hope the data is strong, the FDA moves quickly and AF converts, as well as his hedge fund friends, to fighting cancer. If that were the case, no investment awareness campaign would be necessary. We will see.
Interesting exchange between L. Smith and AF on Seeking Alpha
from 6:54 pm to 10:44 pm on May 28, 2014.
http://seekingalpha.com/article/2242273-northwest-biotherapeutics-management-discusses-interim-data-on-phase-i-ii-trial-of-dcvax-direct
LS clearly proved AF hypocrisy. To me this exchange suggests AF is supportive of big pharma -- because AF clearly touts less impressive phase I data than Direct AND acknowledges tumor stabilization is important -- at least for the companies AF is beholden to.
I do think the amazing Direct results were lost in the shuffle. Pyrr and others helped put tumor necrosis and size back into modern day perspective, but the clinicians are on the frontline. Thanks.
I'll drop it.
You have a point, but even at the end she asked for help getting the word out on the dcvax platform. It's difficult to do when they can't even acknowledge questions were asked about dcvax-l.
DCVax-L is the lead trial. No one knows its status. I submitted a question on it and Linda ignored it and said "that's all the questions." No, it wasn't. --OU
I'm not certain I follow, maybe you were responding to a different post?
For those willing to entertain asides,
This is simply a curiosity that intrigues me. I've mentioned it before, but let me try it from a different angle. NWBO knows how to prepare, train and open clinics for DCVAX-L, whether they be for blinded trials, open label trials or compassionate use (Israel for example), but they have been stuck right around 51 for some time. Approximately 30 are on hold in Europe for reasons yet to be determined. What is the reason?
For purposes of this discussion, please eliminate the possibility of a futility finding in the first or second DMC efficacy reviews.
Here is my list. They are not in personal preferential order.
1. Awaiting German price point announcement?
2. Awaiting DCVAX-L 1st interim DMC efficacy recommendation?
3. Awaiting determination on whether clinic trials will be open label or blinded?
4. Awaiting internal FDA communication after FDA reviews AA application from NWBO sponsor (or CRO) writing team?
5. Awaiting FDA-PEI communication on first review for pseudo progression analysis?
6. Awaiting direction for possible NWBO trial expansion on primary group. (Germany is not going to include Pseudo-progression group in any trial -- only primary group)?
Yep, yep and yep.
Good point. They might avoid a dose escalation phase in a 2b if the phase I/II demonstrate the lower dose works just as well as 15 million, and the 15 million is safe. Thus, for example, they could give 7 tumors 15 million total.
However, by injecting several tumors, the dose plus immune response may have unknown synergy, thus caution against a storm might be preferable. It's definitely a question left open for discussion.
Consequently, I think any future trial utilizing multiple tumor injections per treatment date vaccination will likely have dosing escalation. Maybe something like 1-10, 11-20, 21-30 (just guessing for now). Phase II will not have a slow period, but any phase 2b with multiple injections per treatment sessions probably should. IMHO.
Flip, where do you think Smith deduces they will treat patients with operable, less advanced lesions who will respond better going forward? Perhaps via the fact that L was used to treat rGBM initially (among others), and then focused on the more responding newly diagnosed GBMs for their Ph III? -- Pyrr
Of course it's a study man. If you think they are starting a new study in the middle of 2014 to help approve the current trial, in the words of some burned out rock musician, "you've got another thing coming."
You missed my point. I don't think they are going to use the data from the extended access program for approval. Of course the program is for very ill patients.
Expanded Access.
The extremely recent Expanded Access clinical trial program added by NWBO (with FDA approval) for previously denied DCVAX patients may be connected in spirit to Expanded Application.
In 2012, as many of you know, the pseudo-progression group was included in the DCVAX-L trial. Years ago, this was not the case because pseudo-progression was thought to be cancerous tumor growth -- instead, it was inflammation and tumor necrosis. Previously excluding this group was a mistake, and that is why the group was added in 2012 -- to expand DCVAX-L application.
Now, take a mental flight over to Germany. Their hospital exemption program is not placing restrictions on treatment for this subgroup, and Germany has in fact increased the H.E. application for L to many different levels of brain cancer. Germany will treat but not add pseudo-progression patients to the trial in Germany. Let me suggest that Germany is doing that for 2 reasons. 1. They know L works very well on pseudo-progression patients from clinical work done in Cologne and in the L trials; and therefore would not want to give patients placebos, and 2. They do not want the trial slowed down with a new group that would ultimately get the treatment anyway both through the H.E. program, and/or after full approval with (or possibly w/o need of a) line extension (which may indirectly influence the FDA to forego demanding a trial expansion on the pseudo-progression group).
Now fly back to the United States. The recently added expanded access program (see clinicaltrials.gov) is in fact expanding application to a group (defined slightly differently) that is not in the trial. Not unlike Germany's tact.
What might this mean for the double-blind L trial? Remember, the pseudo-progression group is a tertiary (third) endpoint. I'm pretty certain the FDA and NWBO would be happy with a trend-line to bolster the primary group analysis.
Reefrad inquired, why not keep the pseudo-progression group trial going and move forward on AA for the primary group? My take on it is that they already are moving forward on AA and thus are continuing the trial for both groups so 2 things can happen. The clinical endpoint matures to confirm the surrogate endpoint in the primary group -- hopefully very close to the time AA is granted thus gaining full approval. The pseudo-progression group hopefully gets enough data to establish a trend-line. I don't think they will wait for perfect maturity in the tertiary group before halting the entire trial for efficacy. If the AA process is afoot "behind the scenes," I do not believe there will be unnecessary delay.
Good point. I knew my analogy taken too literally might be misinterpreted. I gave fair warning, but I'll try to abstain as I know it grates on scientist's nerves.
I very much applaud the quick response team-like effort the board put together after the "blog" -- as I think Pyrr accurately referred to AF's hit comment yesterday. Something very powerful occurs when individuals within a group resolve to utilize their collective brain trust, all the while retaining independence, to work toward wise solutions.
Nice example. Thanks. Let me suggest just a slightly different emphasis/conclusion regarding the present value for this prior case study. Eloxatin was used as an adjuvant -- as opposed to replacing standard of care. Still, while the therapy did not replace the standard of care (only added to it), your example is one more arrow in the quiver to demonstrate independent 'clinical' value for disease free progression, and therefore, progression free survival. Likewise, while we hope for S.O.C status for Direct, as Linda states, 'THERE IS NO STANDARD OF CARE FOR THE PATIENTS CURRENTLY BEING TREATED WITH DCVAX-DIRECT.' Thus, Direct can be thought of, for analogy purposes only (don't take me too literally), as an adjuvant to earlier in time treatments -- when we are speaking about inoperable cancer. (Of course, in reality, Direct is/will be a stand alone treatment for what were previously untreatable diseases.)
Great work by everyone. See you mañana.
Thanks Evaluate. Very Accurate, imho.
Thanks for sharing your astute analysis.
I wish I could stick around to discuss your amazing find, but I'm out for a few hours. I trust you'll have it all figured out be the time I get back.
Ou, I hope we get updated on L soon.
From the sounds of it, they might inject multiple tumors during each treatment in a phase IIb and/or phase III. It sounds like they are very excited to do that.
Dr. Chuck. Good call on enrollment screening distinction.
Wait a minute. A while back, didn't you say you thought there was something to DCVAX? Maybe I'm thinking of someone else.
Somebody with a bit of funds just redrew the last 7 months graph (pattern) over past hour.