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Transcript Big Biz Show Pt 2 Aug 18, 2023
This is one of the few Big Biz's where Les actually says anything newsworthy. The quote about order of RAs apps is in here, but also an interesting reply to Sully's partnership question near the end.
Sully: Big Biz Show continue with Les Goldman, Northwest Biotherapeutics, symbol NWBO. Les, I’ve got another question for you, so what so what is the next let's say six months, 18 months, five years outlook for Northwest Bio considering you just got back from ASCO, all the findings there you know you've sort of enumerated, you know kind of the eye-opening stuff that's going on here, so what's next? Are we going to continue the research, are we going to an FDA sort of arc of a story where we're getting close, because it's obviously exciting. I'm gonna get a million emails from people asking when can we get this here in the U.S so talk about that a bit.
LG: We do have this prevention treatment program and may need to go to the UK to initially get it made but a recent license we got to use our facility that we built for commercial operation and it's been licensed to allow us to ship anywhere now in the world, if you call our offices there is a backlog but we can still get a hold of it – we’ve got a waiting list at this point but more significantly we are in the process of finalizing our applications. The first one will be to the MHRA in the UK which is allowing us to do this specials program even before we file, but we're we're getting much closer to being finished up with 1.7 million pages long it's got 27 modules uh it's being double checked now to make sure that it’s completely consistent. So we'll be applying there, and we'll be applying then to the other places that gave us permission to do the trial, that was four different countries including the UK, including Canada, and including Germany and we'll be filing in order in each of those places for a commercial approval and then we will go into operation on a completely commercial basis.
I think the prognosis is very exciting and that we've shown the positive results in in in the compassionate treatment, specials program and we're also dealing with issues we're relating to our not as high as we believe we deserve, value in the marketplace because of interests that would rather see us not succeed; we're cheaper, we're more efficient, we're non-toxic. I would have to add it's already been shown that in combination with certain other products that have been produced which have no effect on solid tumor cancers we enhance the result of what we get when we put it in combination with others, and we'll be doing plenty of that as well.
We also have a product for inoperable tumors where we take the magic formula if you will, and together with MD Anderson in 2015 we ran a Phase I/Phase II trial where we developed a MRI guidance, or CAT scan guidance of being able to take a very thin needle and inject it to find the mothership tumor in a given body, and then put the stuff into the tumor with this very thin tube which is quite non-invasive, but can be guided by the things that you can scope, any one of the ways you could do x-rays. We got very good results on that and then we got the same safety results, which is basically no toxic side effects, and we'll be developing that product as well with further trials.
So there's a lot of activities lying ahead to move this first one, which was our lead item because frankly these trials all cost a fortune. For example if you're going to do prostate which we also have something that works on, to do a Phase III trial can take six or seven years and it costs $800 million. Unfortunately you die a lot quicker and you can measure the results much quicker with GBM so we picked GBM to be our lead, and we're getting we're getting near the end – others are working on it but we're the first.
Sully: Hey Les, last of all will you take this to the finish line or this is this one of those risk aversion models where a bigger Pharma company will come in and take it to the market or do you guys intend on taking the market yourselves once you get there?
LG: Well, if you're asking for absolutely everything, that would be a very big menu I think with our 70, with our 90 sites and 73 doctors we have a pretty established infrastructure for GBM. The fact that it works on other things means, I think it all depends on who might want to team up what they want might want to pay in the future.
Sully: Good stuff, thank you so much
Penn Cancer CME Event Transcript
https://vimeopro.com/ajievents/brain2024/video/910907300
11:20 am – Overcoming Barriers to Extend Survival: Promising results of clinical trials for glioblastoma
2:38: Dr. Steven Brem
First is a trial patients are very aware of was completed, four countries, multinational trial, 90+ centers, 331 patients, centered on Linda Liau’s work at UCLA, they have SPORE there and again Linda Liau and Robert Prins did, Tim Cloughesy and many others, lots of lab work that was developed. Dendritic Cell actually started some of that work, North - I cannot name the company, but some of the trials were first done at the University of Pennsylvania on ovarian cancer. It’s a professional antigen presenting cell which is very attractive, that what dendritic cells do is they sense novel antigens so it should be the ultimate in personalized medicine because of the heterogeneity, so it’s attractive.
Ken Adalpe was named earlier he’s a neoro-pathologist at NIH now and Galerah Zeta who is chair of neurosurgery at University of Toronto did an unbiased study of 33 trials for high grade gliomas and dendritic cells and came to the conclusion that is more probability than possibility that in the near future cytotoxic therapies and immunotherapy would form that 3-prong approach that will improve clinical outcomes.
This trial was finally published last year. It’s awaiting review by FDA (transcriber correction - MHRA, not FDA) and it showed an increase in survival, overall. It was controversial because we used external control group, contemporaneous control, and in talking to Dr. Liau it was more of a matched cohort trial rather than a true typical prospective randomized control trial. It also was a crossover trial so nearly every patient got the vaccine up front or on recurrence. I’m lookin at Sihosh Mulhan (sp) he looked at our Penn series and independently came to the conclusion that there was a survival benefit, but again with matched controls.
Interestingly when you do these hazard plots, as expected MGM-methylated did quite well, older patients did well also, and those with some minimal and even significant residual disease had a survival benefit that was not expected, we don’t have time to go into all of the implications but those are the observations. It was especially important that patients with recurrent GBM, as we know, that’s an area that is difficult to treat in the clinical trial showed the best survival, so that was important. Talking with Linda quite a bit, what patients here want, the Steve the Harry, are not interested in statistical benefit for two or three or four weeks or months, they want a cure, which is an immune approach that’s what you should get because it’s a drug that keeps on giving or you train, you harness the immune system. There wasn’t a significant increase in longterm tails, we didn’t see the kind of tail we’ve seen in melanoma, Tauti, 35 to 50% but it’s a step forward. This is the statistical evidence that I won’t go into. (showed a slide that rated trial designs with this trial the 3rd level just below placebo controlled design).
What is very exciting that is a buzz in the brain tumor community is work that Dr. Liau presented at the SNO meeting over a year ago, in the combination with checkpoint inhibitors, so we think it’s not just going to be the Army or the Navy but it's going to take this multi modal approach, just like you use in the OR (?), some kind of combination therapy and so when you use the checkpoint inhibitors you start to see that significant tail that we are going for and that’s important to get at.
100% Grade III brain tumor patients are still alive. (Between six and ten years). (n = 4)
There were 4 lower grade glioma patients still alive last Feb and they could have those OS's updated. That is all. Not a big deal.
How many shares has Boynton bought on the open market?
The five-year anniversary of the 2018 NWBO Annual Shareholders meeting will on Feb 2, 33 days from today. On the date of that ASM I owned a whopping 50 shares that picked up after looking for the next frontier in cancer immunology following my sale of Dendreon shares after Provenge was approved. I only followed NWBO from afar, and after watching all of the sordid events with the company in the 8 years I was holding those shares, my attention to the details drifted and I was considering selling and eating the loss. Then, later in the week after this ASM I read IkeEsq’s transcript, post #212334, and then listened to the call – which was a whole different experience than reading the transcript. The defiance, resolve, and confidence was palpable. I started digging in and researching to better understand the situation, and then I went all in.
The share price was .23, but whether that was a good move or not is still undetermined as I haven’t sold a share, in fact, I’ve bought significantly more. I know what our board critics will say about the quotes below; mocking Les, or (with good reason), that it was 5 years ago and 460,000 posts ago, and we are still waiting for DCVax-L approval for GBM anywhere in the world, forget anything else. I admit I’m an NWBO ultra-optimist, and I cling to the Buffett axiom that the stock market is a vehicle from transferring wealth from the inpatient to the patient, and yes, I still cling at least a bit to some of the quotes from that day five years ago:
(LG) "Let me just add one thing, we're always thinking about this. As part of my answer before, there will be programs and they will involve numerous activities. But we don't roll them out one-at-a-time, it'll be part of a total package." (LP) "We can't talk about that."
(AB) "The only thing I would add, is we have been at this, I have for 25 years and we will never give up until this is available to all brain cancer patients, and that will happen."
If 78 year old Dr. Alton Boynton can wait 30 years. I can wait a few more months. Good luck in 2024.
Patience and patients,
Frogg
Let’s see a Gotundme for DCVax from 5 years ago where the patient is still alive
The compassionate use case slides are interesting too. Both patients are alive and doing well in 2023. $NWBO #DCVax-Lhttps://t.co/987syOk0Qe pic.twitter.com/P7AkY7n3P6
— Henry (@HenryMuney) March 16, 2023
SNO 2023 DCVax-L discussion transcript from PeerView X account, courtesy ATLinsider.
Note - I did the best I could with Dr. Ashkan's accent.
1:03:48: Manmout Ahluwalia: …there is also work with DCVax which Dr. Brem was involved with that study. Dr. Brem, do you want to highlight the data from that…
Dr. Stephen Brem: We have an expert, Dr. Keyoumars Ashkan from London who is the second author to Linda Liau on our paper in JAMA Oncology this year and I was talking with him before the meeting and things are moving forward, and…do you want to comment?
Dr. Ashkan: Thank you very much Steve. Yes, most of you may have heard about DCVax which is a personalized form of treatment. What was very specific in Dr. King’s presentation was that the many difficulties of glioblastomas is that they are very heterogeneous – no two tumors are the same. So what does that mean? So surgical therapies – and I’m a surgeon – can never be the answer because we cannot resect every single cell. You’ll remember that there were cases of spinal cord GBM, and people transacted about the core, and guess what? There is still GBM many many years later. And secondly because they are so heterogeneous the blanket of treatment, radiotherapy, chemotherapy cannot work because you are dealing with an extremely difficult tumor. The way to address that would be to make the treatment totally personalized to that patient. And in my mind there’s nothing stronger than using the patient's own tumor to produce the treatment, and there’s nothing stronger in my mind than immunotherapy, just like we managed to achieve with COVID. So in view of that you may have seen the results which were published last year in JAMA Oncology which showed that in newly diagnosed GBMs there was an average of a 3 month overall survival benefit compared to external controls, and in the methylated cohort that was 9 months. There was also in recurring GBMs, there was evidence of survival benefit over 6 months and was the first study in 28 years to show an actual benefit in recurring GBM that we haven’t seen elsewhere.
So obviously the next step is to get this drug approved in the UK, where it seems a bit simpler, more efficient pathway to approval which is good news, and we are trying to get the drug approved first in the UK and then beyond that we can move on to the US’s FDA, ect., and so as we speak we are preparing submissions to the MHRA, which is the UK version of the FDA, for regulatory approval and hopefully in the next few months we will hear back. So that was a very quick statement, thank you very much.
Worse, the data itself has issues. The DC P3 was far more selective in patents. Specifically requiring intent for near total resection. The JAMA paper shows that in the ECAs those with near total resection lived as long as DC trial patients.
Interestingly, despite this significant residual disease, the DCVax patients had a mOS of 17.5 months vs. 14.2 mOS for the ECA (3.3 more). There were also 9 of those patients still alive at 5 years, compared to 1 out of 1366 at 3 years in the ECA.
Senti, you are a gem. If you ever leave this board I'm out.
The Company anticipates submitting the MAA in approximately the next 30-45 days.
Brown's Dendreon example is particularly rich. He knows the reason Provenge hit stat sig vs. crossover "placebo" is because "late" Provenge in recurrent PC fared significantly poorer than did "late" DCVax-L in recurrent GBM. Another in the many attempts to obfuscate the outstanding DCVax-L rGBM results.
Think about that. Purposely trying to denigrate a drug that achieved unprecedented success in a cancer indication that has no good treatment options -- which is an understatement considering that for rGBM there is no SOC beyond "try whatever you want" or making the patient comfortable in their final months/days.
Ex likes to throw out the resection imbalance theory to explain the DCVax-L advantage in the trial vs ECAs, but that's built on some fuzzy assumptions.
How close is the -L trial population to the the near total resection population? One would assume very close as they had intent for near total resection.
There is actually a greater survival advantage in patients with significant residual disease (SRD) compared to minimal residual disease (MRD). As a surgeon we always taught and we thought that taking out as much of the tumor as possible leads to a better prognosis, and that still is the case; you see in the MRD group that survival is still longer than the survival in the SRD cohort, but the relative survival advantage is greater in this group. What this kind of suggests is that perhaps…one thing that dendritic cell vaccination that we know it does is that it gets T-cells into the tumors, and perhaps in order to have a more diverse repertoire of antigen presentation in epitope spreading, there may need to be some residual tumor still there so T-cells that are still there, once they get into the tumor and get activated there may need to be residual tumor there to enhance the immune response and promote epitope spreading.
Transcript Les Goldman 9-26-23 BigBizShow
Part II next Tuesday
https://www.biztalkradio.com/players/individuals/
25:18
Sully (Host): We are talking with Les Goldman, from Northwest Biotherapeutics, of course, and talking about their therapy for GBM, which is the most horrible type of brain cancer one can be diagnosed with, and we left off when we last spoke with him talking about life expectancy if you get this death sentence, and I know that biopharma firms and doctors hate to use that term, but it really is horrible, average 16 month lifespan, and with their therapy you’re talking 5 years plus. Let’s get back to that conversation. Les, when we last talked to you we were talking about life expectancy so let’s get back to that, because that’s what we're talking about here right; not just quality of life but life expectancy which is a total gamechanger and potentially not just for GBM. Talk about that a little.
26:04
Les Goldman: You left out one important thing, which is, the treatment is nature’s way which is the opposite of chemotherapy which poisons you. It’s non-toxic, so you can get the shot in the arm and go back to work that day and the worst thing that can happen to you is a slightly elevated fever of a degree or two the first night after the shot, and that’s it. That’s mostly what’s been experienced. And as I was explaining, our objective in the many decades that we have been working on this is to get really good with cells, which I’ve already explained, and then get a validation, which came from the Journal of the American Medical Association (JAMA) oncology journal, which is one of the top-ranked journals, and they concluded that our vaccine was clinically meaningful and led to a significantly effective extension of survival for both newly diagnosed and recurrent GBM and had a very positive safety profile and a long tail of survival curve. And…
27:23
Sully: Stop right there. Mention again because I want to be sure…
LG: …and the third thing was to go after the guys who have been shorting us and keep us down because of the anti-competitive sense of some financial interests - understandable in a capitalism – that didn’t want to compete with something that was easier to make, easier to take, and lasted far more long.
Sully: Stay right there…
LG: …those are the three main stools of the platform we’ve been working on and we are getting to the finish line.
Sully: I want to stop and go back there, because I don’t want anyone to the miss the fact that when he was reading that excerpt, where it came from. This is not an industry rag that we are talking about. This is not a local newsletter or a blurb online. This is JAMA. Once again Les, I want you to say it one more time because this is significant. What you were just excerpting was from where?
LG: The Journal of Oncology which is published by JAMA which is the Journal of American Medical Association.
Sully: Peer-reviewed by the way, you can just write an article and throw it in there, takes a little time a little bit of research to get there. Mike had a question about compassionate use…
Mike (Host): Les, what is the compassionate care plan with you guys right now?
LG: We did this trial in 4 countries, 90 sites, and the country that has been the most excited about us, and all of them are because the results are so much different than anybody has ever seen, is the UK, where ever since Brexit they have been determined to be the leader in very serious diseases that don’t have a lot of good treatments, and in that vain, the first to take advantage of their early approval, which used to be 11-13 months, and now is 5 months, was Pfizer on their COVID vaccine, and again the criteria to qualify for that program is that you got to be treating a serious disease, and you also have to have no meaningful treatments. That qualifies us for what you’ve got there.
The next thing on my list of accomplishments is as Sully stated a little earlier, we have announced in the last couple weeks that in the coming weeks we will be filing our first application for commercial approval in the UK. We’ve been working on that for 16 months and we are getting very close to being finished. More significantly, they gave us a license, because we’re non-toxic (in part?) to do compassionate treatment and we’ve been doing that in the UK for about 3 and half 4 years, and they gave us permission for the new commercial plant which we’ve built, which in order to even put your application in it’s a pre-condition that you get your plant certified to manufacture it, because they want to know before they look at the drug that you’ve got a place to meet all of their standards for manufacturing. It was March of this year that we got the permit and the license to move forward along with the license for the compassionate use program - they call it specials. We’ve been doing that, and the only place to go with an ongoing ability…it’s a very exciting thing to do because you get ready for full commercialization because you get real world experience…the trials are very structured, and this gives us everything you’ve ever seen. Overall we’ve treated just shy of over 800 patients. In the trial there were 331 patients and the rest over the years were compassionate treatment, we even did a compassionate treatment program in Isreal before we were in the UK. So that’s a quick rundown on that answer…
Sully: With the time that we have left I want to talk about something that has gone on with respect to this algorithmic trading and naked shorting, the digital version of the naked short, and I think it’s important to talk about this because, as I said before, I’ll give this little lesson every time I talk, you can’t sell your home before you own it, you can’t sell your car before you own it, but you can sell stocks before you own them, it’s called short selling. It’s been part of our investment culture for a long time and this is how it works. You tell your broker that I want to borrow some shares that I don’t own, of $AAPL, let’s say, and I want to sell them the first day. I’m selling the borrowed shares and getting the cash. I’ve got cash for something I don’t own yet. I’ve got to deliver cash or shares two days from now. Hopefully, I bought them for $100, that they go down in value - I’m betting against the stock. It goes down to $80, great, I’ll buy them back for $80 and I’ll keep the $20 for my proceeds. The problem, the borrowing section is the tricky part. Naked shorting is when there’s no shares actually being borrowed, they are just creating them out of thin air, and in 20 days when the shares have to be delivered from broker to broker, the shares aren’t there.
LG: Counterfeit shares is what they are called.
Sully: It’s called a failure to deliver. It’s abusive short selling and it’s wiped out billions of dollars in market caps, company from Gamestop all the say down to penny stocks. With this stock, and I’m going to say this so Les doesn’t have to, billions of dollars were taken out of the market cap over the course of a couple days. Les, I’ll let you take it from there, because herein lies the lawsuit and we have to talk about where you guys are at there, because you guys are leading the charge on something that has to happen. I believe you will change the way stocks are traded. I believe you will change the way this mess happens, so that companies, innocent companies, do not lose market cap, and I want you take it away and talk about that a little bit.
LG: If you watch current events, you understand that commenting on an existing litigation is probably not something that’s wise for either a plaintiff or defendant to do. By inference, I will simply say that on December 1 we filed a suit against the top 7 market makers. The bottom line is that it is mostly retail investors who don’t realize how it’s done and how this is going on, so we would hope that we will pursue this suit and that there will be substantial damages.
Sully: We will leave it there. Les Goldman, we will see you next week. Les Goldman is the general counsel and senior VP of Northwest Biotherapeutics, nwbio.com, their stock is $NWBO.
>>Nearly every single patient will have relapse of their cancer; the 5-year overall survival is less than 10%.<<
Way less than 10%. We know that with our trial in the treatment group 25/232 survived 5 years (10.7%), and even though most studies in the ECA didn't follow patients 5 years, the KM estimate was 5.7%. We know from recent reports that some of those patients in our study are still alive -- based on the curves and Dr. Liau's comments on "patients in remission" it's likely that most are still alive. *
This study supports those numbers:
However, despite standard Stupp treatment, the prognosis of most GBM patients remains poor, with a median survival time of 14.6?months, a 26.5% 2-year survival rate, and?<?5% five-year survival rate [2].
(slide 20, 23:35) This one was very surprising to us. There is actually a greater survival advantage in patients with significant residual disease (SRD) compared to minimal residual disease (MRD). As a surgeon we always taught and we thought that taking out as much of the tumor as possible leads to a better prognosis, and that still is the case; you see in the MRD group that survival is still longer than the survival in the SRD cohort, but the relative survival advantage is greater in this group. What this kind of suggests is that perhaps…one thing that dendritic cell vaccination that we know it does is that it gets T-cells into the tumors, and perhaps in order to have a more diverse repertoire of antigen presentation in epitope spreading, there may need to be some residual tumor still there so T-cells that are still there, once they get into the tumor and get activated there may need to be residual tumor there to enhance the immune response and promote epitope spreading
What we do not know is if extent of resection of resection can explain the results
Dr. Toms of UPenn in the LifeSpan press conference on DCVax-L: "As Dr. Elinzano pointed out, the data suggests about a three-month survival increase in the patients who got this vaccine in overall survival, but the thing that really stood out in this was the tail – the number of long-term survivors. In communications with Dr. Liau, she has a few patients who are 17 and 18 years out under this treatment, which is longer than any survivors I or Dr. Elinzano have. I have a couple of 12 year survivors at this point."
I wish I had the QandA video with Liau and Musella, but as far as I know it is not accessible anywhere. If I had known that I would have typed really fast!
One of the questions that keeps coming up regarding that is around how many DCVax-L patients are still alive -- seems like an important thing to know. I went back and looked at what people were live-posting here during the QandA and this is what I got:
Flexroy
Re: Survivor2012 post# 544220
Monday, December 05, 2022 9:26:55 PM
Post# 544225 of 578052
She said about 60 in total. Inc compassionate use and other phases I believe. She said 25 in this one. Then another 25. Then a dozen in compassionate use.
beartrap12 12/05/22 9:58 PM
#544273 RE: Flexroy #544225
That’s exactly what I heard, Flexroy. 60 total alive from all trials and compassionate care, LL estimation.
Thus DCVax-l might make drugs like Keytruda safer.
Interesting. When the trial is complete this will be interesting to see; if true that would be huge.
Thanks Flipper. If you don't want to take the time to watch the video linked, here's the relevent transcripted comments from Dr. Liau:
"This is just some preliminary unpublished data on our trial at UCLA whereby we are combining dendritic cell vaccination with PD-1 inhibition, and what we are showing is that…interestingly, when we give PD-1 inhibition neoadjuvantly – before vaccination – you actually get a survival curve that is better than just giving PD-1 alone, but if you give PD-1 inhibitor after dendritic cell vaccination you can boost that survival rate up to greater than 50%. Again this data is very preliminary, we are only half way through this trial so we don’t have final data yet but I think it’s encouraging in the fact that we probably can combine vaccine therapies with immune modulators to hopefully get a positive response for our GBM patients."
Been done here, many times. It's from the JAMA publication Figure 3.
https://jamanetwork.com/journals/jamaoncology/fullarticle/2798847#figure-table-tab
Maybe someone else can help. I'm only interested in DCVax-L science based transcripts.
It's just the usual BS. JDUK and others who throw this out are hoping the reader doesn't know that 64 of the patients randomized to placebo got DCVax-L, that those patients significantly outlived their external control counterparts -- at 24 mo., 13/64 alive in trial vs. 13/640 in the EC cohort, with a stat sig p-value of .001. Inconvenient truths.
Senti, whenever I scan this board trying to figure out what to read and what to ignore I always know that when I see your name and click I'll get common sense and great insights. We appreciate you!
There was some great stuff in the QandA -- If I had known it would never get posted I would have recorded it. Bummer.
We got something from LL on this on Dec. 5. Unfortunately for reasons we haven't been told the Q and A from the Dec. 5 interview was pulled from the posted video. Luckily there were some folks here live posting that provides some record of what she said regarding DCVax-L patients still alive:
Flexroy
Re: Survivor2012 post# 544220
Monday, December 05, 2022 9:26:55 PM
Post# 544225 of 578052
She said about 60 in total. Inc compassionate use and other phases I believe. She said 25 in this one. Then another 25. Then a dozen in compassionate use.
beartrap12 12/05/22 9:58 PM
#544273 RE: Flexroy #544225
That’s exactly what I heard, Flexroy. 60 total alive from all trials and compassionate care, LL estimation.
The Musella interview when Dr. Laiu showed the graph with pembro both neo-adjuvantly (pre DCVax) which was OK, and adjuvantly (after DCVax) which was incredible, was on Dec 5, 2022.
Transcript: Neurology Journal: Dr. Bevel Interviews Dr. Liau
Dr. Linda Liau joins Kate Neville on Neurology Journal Podcast, Mar 2, 2023
0:27
Dr. Nevel: Hi, my name is Kate Nevel and I'm a neuro-oncologist at Indiana University and today I'm delighted to be talking to Linda Liau, professor and chair of the Department of Neurosurgery at UCLA, about her recent study and publication “Association of Autologous Tumor Lysate-loaded Dendritic Cell Vaccination with Extension of Survival Among Patients with Newly Diagnosed and Recurrent Glioblastoma,” a phase 3 prospective externally controlled cohort trial published in JAMA Oncology in November of 2022. Dr Liau, thank you so much for being here today and talking with me.
Dr. Liau: Thank you for having me.
Dr. Nevel: So I remember when this paper was published because the neuro-oncology community was at a national meeting and you know kind of wondering what this would mean, and we'll get to the details later, but since this paper has been published I've have had patients calling emailing me asking me about DCVax-L. So for our listeners out there what's the most important thing you think clinicians should tell patients when they call asking about this study?
Dr. Liau: This was a phase three non-randomized prospective cohort trial of autologous vaccine for brain cancer that has shown some promising results. However it is not yet FDA approved so it is not currently available in the U.S outside of clinical trials. And you know further clinical trials are ongoing using this agent.
Dr. Nevel: I think in order to better understand the results of the study, which we'll get to, we first need to go over some of the methods and design and how you analyze the results. So do you mind giving us some background on that the study was initially designed as a phase 3 double-blinded randomized controlled trial with the crossover arm. However as the trial is underway we began to realize that because of the crossover arm, eventually about 90 percent of all patients received DCVax either at new diagnosis or at presumed recurrence. There are actually several patients that you know subsequently were probably found to have pseudoprogression, so in the end it was depletion of the placebo control arm. Therefore before the trial was ever unblinded a prospective Statistical Analysis Plan (SAP) was designed to compare overall survival in the newly diagnosed cohort and the recurrent glioblastoma cohort of patients who are treated with DCVax with contemporaneous match external control populations from control groups of other formal randomized clinical trials. Because of the crossover arm what we essentially we had were two groups of patients, one who got DCVax early, at new diagnosis, and one who got DCVax at first recurrence. Those were kind of the two populations were left with with this trial, and that's why it was controlled to external controls. So yes it's not a randomized controlled trial but that is the background of the methods of the study. The comparator trials were chosen based on predetermined criteria and a broad ??? was conducted using these criteria, which included contemporaneous study time period, a similar KPS and age groups, reported outcomes with overall survival, and you know various other criteria that are listed in the paper. So based on that there were five newly diagnosed studies that were chosen for the comparator population and ten recurrent glioblastoma studies that were chosen for the comparative population for that group, and then our statisticians did an internal validation using various specificity and sensitivity analysis. So overall that was the methodology of the study and you know I'm aware of the limitations of using external control populations, but given the conduct of the trial and the depletion of the placebo arm we felt that this was a comparison that made sense, and with its known limitations.
4:47
Dr. Nevel: I think that brings up an interesting topic that maybe is beyond the discussion for today about using these externally controlled cohort populations in cancer research specifically because of some of the the reasons that you mentioned, that the ethics behind not offering an intervention or ability to cross over for patients with cancer especially patients with incurable cancers.
5:13
Dr. Liau: Yeah, correct. And at the time of the trial initiation it was actually quite difficult to get patients to enroll because patients don't want to be on the placebo arm and so the crossover arm was placed to allow for that option, but retrospect the comparators were for this trial
Dr. Nevel: With that could you please review the most important results of your study
Dr. Liau: I think the most important results of the study are that patients with newly diagnosed glioblastoma receiving DCVax had a median overall survival of 22.4 months from the time of surgery, 19 months from the time of randomization, and the patients with recurrent GBM had a median overall survival of 13.2 months. And these survival statistics compared favorably with that of the external control populations from over 1300 newly diagnosed glioblastoma patients and 640 recurrent glioblastoma patients from various other published clinical trials. But what I think maybe even more interesting is the long tail end of the survival curve and some of the subgroup analysis results that came out of the trial. For instance the median survival of the MGMT methylated patients was over 30 months, with almost 20 percent five-year survival. It was interesting in that the majority of these patients surviving over five years are surviving without recurrence, which in the field of glioblastoma is actually quite unusual. So I think it does give us some information in aide in terms of how to design future clinical trials and perhaps how to stratify patients for immunotherapy trials and potential biomarkers.
6:54
Dr. Nevel: I found that particularly interesting to the different subgroup analyses and the MGMT group specifically, which we know in general is a subgroup of patients with glioblastoma who in general we expect to live longer and have longer progression-free survival than patients who do not have MGMT promoter methylation present or having what we call an unmethylated MGMT status. Sometimes but obviously more of a benefit you found in your study in that group of patients who received DCVax-L but I was curious if you had hypothesized a mechanism of or physiologic you know kind of pharmaceutical reason why the vaccine might work better for patients who had MGMT methylated tumors?
7:48
Dr. Liau: DCVax-L is an autologous dendritic cell-based vaccine that consists of a combination of a patient's bone dendritic cells which are antigen presenting cells that are cultured from blood cells from the patient's blood and then we put that in combination with a tumor lysate from the patient's tumor that is taken at the time of surgery and the concept is that the dendritic cell or antigen presenting cell is able to phagocytize and process tumor antigens from the tumor and then the cell combination is injected back into patients to activate endogenous T-cells and we have shown from previous pre-clinical and early clinical trials that the use of dendritic cell vaccination with autologous tumor lysates does induce proliferation or infiltration of T cells into brain tumors, which which we think is the initial first step for induction of an immune response in these brain cancer patients. One problem with immunotherapy for glioblastoma is that glioblastomas tend to be immunologically cold – there are no T cells in the tumor, so that's why a lot of these checkpoint Inhibitors and other immunomodulators don't work as a single agent. So by activating the immune response using a vaccine, we're hoping that getting the T cells into the tumor will allow for kind of that initiation of immunotherapeutic response
9:25
Dr. Nevel: Interesting. I guess this would probably be a good time to, if you don't mind, just in really kind of basic terms explain what exactly the DCVax-L is and how it works.
Dr. Liau: DCVax is a dendritic cell vaccine and the L stands for lysate, so the dendritic cells are antigen presenting cells. They're actually normal antigen presenting cells in the body but we've developed a way to actually grow them in large quantities outside of the body, taken from a progenitor blood cells, and these antigen presenting cells are then co-cultured with tumor lysate from the patients tumors; the concept behind that is because of the relative immune privilege of the brain, the dendritic cells circulating around do not typically encounter tumor antigens within the brain, so this is just a way to basically get the dendritic cells together with the tumor antigens and then that itself is a vaccine that's injected back into patients to activate the endogenous T cells. And it's the activated T cells that traffic and migrate into the tumors to initiate an immune response. We have found in our previous pre-clinical and early clinical studies that is something that DCVax can do is, it does induce the trafficking of T cells into brain tumors.
10:53
Dr. Nevel: So we were talking earlier obviously about the methods and design of the study and the externally controlled cohort, and we talked about that as one of the potential limitations of the study. In addition to that, any other limitations or challenges that you encountered conducting this study?
Dr. Liau: The patients treated with DCVax in the study were compared with the control arms of contemporaneous matched external controls who receive standard of care alone. To mitigate some of the limitations using external controls we did use a novel methodology to neural oncology called a MAIC analysis, which stands for Matching Adjusted Indirect Comparison Analysis, which matched patient characteristics between the trials as best we could at the population level. However, we were unable to obtain individual patient level data from the previously published comparator trials so we're not able to do individual patient matching which we are all aware is a current limitation with the use of external controls, so I'm actually hoping that our publication and the discussions around, it will spur the sponsors of these clinical trials to publicly release their individual patient data so that we as a field can further innovate and get regulatory interest in the use of external control arms in neurology and oncology trials. Because for patients with a deadly disease I think there's less and less interest in being the placebo control arm for large randomized controlled trials, especially since the data of standard of care is actually pretty well known from trials that we've done over the past 10 to 15 years.
12:43
Dr. Bevel: On that note for the individual patient data how detailed would the data be?
Dr. Liau: I think even things that contain the typical prognostic indicators – age, extent
of resection, MT methylation, doesn't necessarily need to be terribly complex because quite frankly we actually don't have very many prognostic indicators in the glioblastoma field, but I think it'll open up a way to really get patient level data, and I think the FDA is becoming more open to the use of external controls as the comparator arm for large clinical trials.
13:19
Dr. Bevel: So how do you foresee these results potentially impacting patient care in the future?
Dr. Liau: I think for next steps for the DCVax-L, based on what we've learned about the mechanisms of action and the potential biomarkers of response, we are currently conducting additional studies to look at the combinations of DC vaccines with various immune checkpoint
inhibitors and immune modulators so it can help to further enhance the efficacy, because even though there does seem to be a signal of efficacy with almost 20 percent five-year survival rate, that still means 75 to 80 percent of people aren't living five years, so I think we as a field need to do better. I think there's not going to be a one magic bullet that cures glioblastoma, but having different options available to patients for real world studies of rationalized personalized immunotherapy I think would be useful for the field. So given the very favorable toxicity profile for DCVax and its potential efficacy, I do hope that it can be FDA approved someday and incorporated into testing various combinations, if not the standard of care in the future if these subsequent trials pan out.
Dr: Bevel: So on that note, do you foresee DCVax-L being in a combination randomized controlled trial study looking at DCVax-L with a different agent or another study with temozolomide in a randomized controlled trial setting?
14:53
Dr. Liau: You know one problem with a lot of randomized controlled trials is that it itself is also artificial compared to the real world use of a lot of our therapy. So whether I foresee another randomized controlled trial, I think it depends on the sponsor of the trial, but I think if we are able to get these options out to the community for testing, I'm hoping that there will be greater data that we can generate, because I think one of the problems we have with a lot of these clinical trials of single agents is that without access to the agents it's hard for people to do these combination studies. So I'm hoping that there will be innovation in the field in terms of how we can best move some treatments forward, given the current regulatory as well as clinical trial environment, that kind of limits how we do larger trials with combination therapies.
Dr. Bevel: So patients sometimes, especially since the publication of your paper, they call in, and this is not an FDA approved therapy, but how can they access DCVax-L right now? Is that information you can share with us? Could you talk to that a little bit?
16:11
Dr. Liau: DCVax is currently available for compassionate use in the UK; it was approved by the MHRA for that purpose. It's not yet FDA approved and I think in terms of access to treatments there's the balance between access and also getting more data and validation of efficacy, and I hope there will be a way in the future to be able to do both – to be able to allow patients access to treatments and then I have the neuro-oncology community continue to test agents and come up with innovative trials to prove or disprove efficacy. One problem is that unless you can get access to the agent it's very difficult to do that, so perhaps a way to open access to DCVax before continued testing would be beneficial to the field.
17:09
Dr. Bevel: Absolutely, and speaking just on a broader scope, patient access to medications is such a big issue in many fields of medicine, cancer care included. With insurance and approvals let alone access to things that are not approved for compassionate use, or experimental trial use. It's a challenge. But I appreciate your comments and you being so candid about it.
Dr. Liau: A lot of patients now in the neuro-oncology community, they're just taking a lot of different off-label drugs that have even less proof of efficacy for glioblastoma, but it's FDA approved for another indication and they want to try it, and neuro oncologists are giving it. I guess my hope for DCVax is that maybe it could be accessible so that we can do these studies and allow patients the right to try.
18:05
Dr. Bevel: Thank you so much Linda for joining me and answering my many questions and the dialogue about your study of DCVax-L and the challenges surrounding cancer clinical trial design. I really appreciated our conversation today.
Dr. Liau: Thank you thank you for having me.
Conversely, those who were heavily short after the FDA required a confirmatory trial got burned when DNDN when to $50. Those that recognized that approval didn't mean the company was ready to meet demand and jumped in up near $50 to short made bank. LP has talked about lessons learned from DNDN which has helped me with patience -- I want NWBO to get not only approved but get all that follows right.
This version is a little easier to read:
Al Mussela: Welcome to the Musella Foundation’s webinar series. Tonight’s topic is the DCVax vaccine, and our very very very special speaker is Dr. Linda Liau, who is the chairman of the Dept Neurosurgery at UCLA and professor and Director of the UCLA Brain Tumor program, and is the former editor-in-chief of the Journal of Neuro-oncology. Take it away Dr Liau.
LL: Thank you Al, thanks for having me. I’m going to start my screenshare and get started with my presentation, and I’ll take some questions at the end. So can you all see my screen OK?
AM: Yes, perfect.
LL: (slide 1, 0:50) OK, so today I’m going to talk about the paper we recently published on the Phase 3 trial results and kind of go into a little more detail, about the details of that paper.
(Slide 2, 1:04) Here are my disclosures. (Research grants/funding to institution: NIH, NWBO, Merck. Advisory Boards: Insightec, Inc., ImmPact Bio. Stock Shareholder ClearPoint Neuro).
(Slide 3, 1:11) So, dendritic cells vaccines are really based on the concept of the dendritic cell; the dendritic cell is a professional antigen presenting cell. They are a normal cell in the body and they were discovered in the 1970s by Dr. Steinman, but it wasn’t until the late 90’s when people learned how to grow these cells in large numbers outside of the body. We were one of the groups that started exploring the use of dendritic cells as a vehicle for vaccines. So the concept is really taking the antigen presenting cells and loading them with tumor antigens; in this particular case, the antigens from autologous patient tumors. The cells are then injected into patients and thereby activate T-cells, and these resting anti-cancer T-cells can then grow and proliferate. They get activated and then they can divide and proliferate then go on to t tumor site to attack the tumor.
(Slide 4, 2:33) So, we and others have over the years done lots of pre-clinical studies. We were the first to do the early phase clinical trials using this vaccine, and one thing that we do know is that dendritic cell vaccination does get T-cells into the tumors. The infiltration activation of T-cells into the tumors is a necessary, although not always sufficient, first step in terms of activating an immune response to glioblastoma. We have done several early studies with this vaccine in patients, many of whom are still alive today, and one thing that is consistent among long term survivors is that they do have T-cell infiltration into their tumors.
(Slide 5, 3:27) This is the schematic for the Phase 3 trial. It was a Phase 3 multicenter randomized clinical trial of autologous DC vaccination. 331 patients. The patients underwent screening and surgery. Following surgery they had leukapheresis in order to collect the blood cells to make dendritic cells. The dendritic cell vaccine is essentially the combination of the dendritic cell and the patient’s tumor tissues taken at the time of surgery. Then patients underwent standard chemo-radiation following surgery during which time the dendritic cell vaccine was made. After chemo-radiation patients were randomized to placebo vs. DCVax and they were treated on Day 0, 10, and 20 with the vaccine, and had booster injections every 2 months for the first year and every 6 months for the two subsequent years.
(Slide 6, 4:31): This study was conducted at 94 sites in four different countries including the US, Canada, and the UK and Germany. Just completing this trial itself was quite a feat as you can imagine. There was a lot of logistical coordination that went into getting this trial started and getting treatments to these various sites. One thing it did show is that it is feasible and can be done in a wide variety of clinical settings which I think is a strong point because some clinical trials can only be done in very specialized tertiary and quaternary academic centers whereas this is something that can be more widely accessible.
(Slide 7, 5:23) So this was the patient enrollment. 331 patients. This was initially designed as a randomized controlled trial with 2 to 1 randomization. 233 in this arm, 99 in this arm who got placebo. Of note, even though the trial was initially started in 2007, recruiting was paused for economic reasons following the recession in 2008, so the majority of patients were actually enrolled between 2012 and 2015, so that’s something to keep in mind when considering the comparator trials that this trial was compared to. The reason we compared this to external controls was because of this crossover arm. Because of the crossover arm most of the placebo patients eventually crossed over to get DCVax, and the few that did not crossover, many of those had actually either died or were lost to follow up, so there were very few control patients left for analysis. Basically the control arm was depleted, and that’s why we couldn’t do a comparison to that cohort.
(Slide 8, 6:53) One issue – and we’ve been very transparent about this – is the issue of Progression Free Survival (PFS). When this trial was initially started and the protocol was written in 2007 the endpoint of progression was to be determined by using something called the McDonald criteria. But then, as many people may know, as the trial was underway the field began to realize the problems with using strictly the McDonald criteria for progression, so it went on to the RANO criteria, and RANO was not sufficient so subsequently that has been changed to iRano, and there have been problems using iRANO as well, so now there’s been talk of using modified RANO (mRANO). And the problem is essentially illustrated here. This is a patient who received vaccination, received surgery and got vaccination, and then is noted to have progression based on strict McDonald criteria but this patient was clinically doing very well; didn’t have any symptoms, didn’t have any other issues, and then over time this area regressed on its own without any further treatment. So in this particular case this would have been deemed as a pseudo-progresser but at the time we wouldn’t have been able to know that. During this trial the radiology review was done centrally by two radiologists that were unaware of the treatment cohorts that the patients were on, and in over 50% of the cases the radiologists themselves did not agree. So that of course made determination of PFS a very difficult endpoint. When you have an endpoint that could not be reliably determined that made that endpoint essentially very difficult to assess as a valid endpoint. Even when iRANO came on board – iRANO stands for immunotherapy Response Assessment in Neuro-Oncology – one thing that iRANO required was a follow up scan in 3 months, but the reason we moved from iRANO to mRANO is because, if you can imagine if you are a patient and they saw progression and the response is “well let’s go 3 more months and get another scan” a lot of patients on clinical trials that used iRANO had to be censored because there was a lot of dropout from those trials. So I think the field is still trying to figure out how to determine PFS in an immunotherapy setting in glioblastoma.
(Slide 9, 10:11) With all that being said, while the trial was underway, but before data lock and before unblinding, the Statistical Analysis Plan (SAP) that was submitted to the regulators was designed to focus on Overall Survival (OS) as opposed to PFS. This was the design of the SAP, and essentially because of the depletion of the control and because of the crossover the primary endpoint was then written to include survival compared to external controls. Then as you can imagine, this was a trial done in the newly diagnosed setting, so when patients actually crossed over they were deemed to be patients who had first recurrence. So that group that crossed over were then compared to overall survival in clinical trials of rGBM. This was the primary endpoint and this was the secondary endpoint.
(Slide 10, 11:23) So talking a little bit more about the SAP, the first thing that needed to be done was to match the trials to find the comparator trials on which to compare these patients. This was the selection of the comparators was done by an independent statistics firm based on four pre-determined criteria used to match these trials, which included the contemporaneous time period from which the patients were enrolled into the trial, the similarity with eligibility criteria, and treatment protocols. Using these 14 criteria there were 5 trials that were done around that same time period that were used as comparators. This is a graph showing the control arm of those five trials. As you can see they overlap quite a bit, actually they were consistent in terms of the Kaplan-Meier survival curves for the control arms of these trials. This comprised more than 1300 that essentially received radiation and temozolomide and served as the control population.
(Slide 11, 12:49) In addition to taking these patients in control arm of these trials, one bias that could be introduced if there are different characteristics of these control arms. So we used an analysis called a MAIC analysis, Matching Adjusted Indirect Comparison, this is used quite frequently in health care economics, in population health analysis. What it does is actually tries to compare individual level patient characteristics with weighted characteristics in a population of patients - in this case, the control arms of these trials. This is a way to do as close of matching as we can of these patients when individual level patient level data is not available for propensity score matching. One thing I would advocate for and hope for in the future is that when we do these large trials that the patient level data can be made openly available for comparisons for subsequent trials. I think that would be very beneficial to the field. But essentially these characteristics were a match for each patient in our trial were matched to characteristics of patients in the comparator trials and they were matched for things like age, extent of resection, MGMT methylation and several other factors. In addition to the matching we also did sensitivity analysis to check for comparator differences. There were five different sensitivity analyses that were performed doing each of these comparisons, leaving out one comparator at a time, and even with each of these analyses the statistical differences between our treatment arm and the external control population did hold out to be true. We also did a 6th sensitivity analysis whereby we took out two comparators where it was unclear whether the early progressors were excluded from their trials and only did the comparison to the 3 other other trials where they did, as in our trial, take out early progressors, and those data also showed a statistically significant difference. So basically with the sensitivity analysis the outcomes came out to be the same.
(Slide 12, 15:54) The was also specificity analyses that were done for validation of external controls because as you could imagine one potential bias could be that if using this approach you could erroneously have a negative trial turn out to be positive. So in a way to kind of control for that each of the 15 studies that were used as comparators, the 10 newly diagnosed studies and the 10 rGBM studies, were taken and we took the treatment arms of these trials and compared them to the external control population using the same methodology that we used for this trial. What that showed was that all the trials that were negative in the randomized control setting, you know where these randomized trials are done, trials that were negative were still negative when compared to these external population of patients, and all the trials that were positive, which was only one, the TTF trial, actually did turn out to be positive. So at least with this level of analysis there was some validation that the negative trials, if a randomized controlled trial were done, were still negative and the positive trials were still positive.
(Slide 13, 17:21) This is the baseline demographic and clinical characteristics of the comparator trials, compared to our treatment group, and this is the pool of external control of 1366 patients. Frankly I don’t think we should be subjecting another thousands of patients to randomized controlled trials when the data from these arms are very consistent. The KM curve is very consistent among these various trials. MGMT methylation was very similar, as well as residual disease for the trials that we had those data for.
(Slide 14, 18:27) These were the baseline characteristics for the rGBM patients. In this group there were 10 different trials amounting to 640 patients and the 64 patients that crossed over constituted our treatment arm for the rGBM group.
(Slide 15, 18:44) Here are some additional baseline characteristics for these trials and of our external control patients as well as treatment patients in our nGBM DCVax group as well as the rGBM DCVax group. I won’t go through all the details expect to say that the characteristics were very similar. Of note, we also looked at IDH mutation, because there was the thought that if there were a lot of IDH mutated patients that could be why there was increased survival. The percentage of IDH mutated patients is only 3% in our treated patients which is similar to the external controls.
(Slide 16, 19:33) So this is the data. There was a significantly significant difference in the median OS in the DCVax treated patients compared to the external controls; granted this was not a randomized controlled trial and I realize the limitations because of that, but given the circumstances probably as close a match as we could perform to validate an external control population. One thing I thought was particularly interesting was in the different subgroup analyses which showed even more robust hazard ratios, when we looked at patients for instance who were over 65 or who had significant residual disease or MGMT methylation.
(Slide 17, 20:37) This is the KM curve for the crossover arm, so placebo crossed over meant that the patients crossed over and received DCVax at recurrence, that group compared to the external controls from the external group. One thing I would like to note (went back a slide) is that these tails are actually KM estimates. A lot of these external comparator trials did not actually follow patients all the way out to five years. They ended in less time than that. So these are not actual data on the external controls but the KM estimates based on the statistics. (Back to rGBM slide) With that being said the difference is still significant.
(slide 18, 21:31) This is the landmark survival rates based on the KM estimates for the external control population. Our DCVax group had a 13% 5 year survival in the nGBM setting and 11% at 30 month survival (in the rGBM group). This may actually be higher as many patients are living out past 5 years but we stopped the analysis at a specific time point so this is the KM estimates at 13%.
(slide 19, 22:18) As far as the subgroup analyses, and I think there were some very interesting hypotheses that came out of the subgroup analyses, were somewhat unexpected, and could lead to further study in these areas. One is that there seemed to be a significant survival advantage in patients over 65 who had the dendritic vaccine vs the controls, and that bodes well for this having some effect in these older age group patients. Note this doesn’t mean that the vaccine worked better in patients older than 65, just that it suggests that worked relatively better than the control patients who were over 65. If you look at the median survival here at 15.6% whereas here in the patients under 65 it was 19.6%, so it still works better in younger patients, but relatively better in older patients compared to the external controls.
(slide 20, 23:35) This one was very surprising to us. There is actually a greater survival advantage in patients with significant residual disease (SRD) compared to minimal residual disease (MRD). As a surgeon we always taught and we thought that taking out as much of the tumor as possible leads to a better prognosis, and that still is the case; you see in the MRD group that survival is still longer than the survival in the SRD cohort, but the relative survival advantage is greater in this group. What this kind of suggests is that perhaps…one thing that dendritic cell vaccination that we know it does is that it gets T-cells into the tumors, and perhaps in order to have a more diverse repertoire of antigen presentation in epitope spreading, there may need to be some residual tumor still there so T-cells that are still there, once they get into the tumor and get activated there may need to be residual tumor there to enhance the immune response and promote epitope spreading. This hypothesis perhaps needs further validation but I found that to be very interesting in this case.
(slide 21, 25:09) Another subgroup analysis that showed a significant survival advantage were the MGMT methylated patients. In this subgroup the median survival was 30 months. What I thought was particularly interesting was that when these patients got to about 3 years the majority of these patients continued to live on, not just continued to survive, did not have progression. It could be that in this subgroup of patients there is a % of these patients, roughly 20%, that do have a significant long-term survival advantage with DC vaccination. And why it’s more effective in MGMT methylated patients we don’t know; MGMT methylation might be a surrogate marker for something we have yet to discover. There have been some reports that suggests that methylated tumors are more hyper-mutated so they may have mutations to induce an immune response.
(Slide 22, 26:27) These are the relative percentages of long-term survivors in the overall DC vaccinated patients. At the end of the day it turned out there was not a clear cut prognostic advantage to some of these prognostic indicators particularly as related to age or IDH mutation. With MGMT methylation you can see there is a greater extent of long term survivors in the MGMT methylated group.
(slide 23, 27:07) So, in conclusion, personalized autologous tumor lysate-pulsed cellular vaccines such as DCVax appears to be safe with minimal toxicity, and was feasible to administer in >90 sites internationally. In nGBM there was a statistically significant difference in median survival in both the nGBM and in the rGBM patients. Again, this was compared to external control populations, this was not a randomized controlled trial although the external control populations were matched as well as we could in this situation. It’s probably the best we could have done given the data that we had.
(slide 24, 27:59) Long term survival, I think this is even more interesting, it was significantly increased in our GBM patients who received DCVax; and it wasn’t just 13% long term survival, it was actually longer term survival without progression, which actually was quite interesting. Again there seems to be a significant long term survival tail, more than 5 years without recurrence in the MGMT methylated patients.
(slide 25, 28:34) So, I think that data, it is what it is. It is level 2 data, it is compared to an external control cohort, and in terms of where it will go next, that’s still yet to be determined. But I do think that it is certainly a first step to really, hopefully getting to more significant longer term survival in GBM patients. This was actually a review written by these authors a year or so ago, and it shows the potential role of dendritic cell vaccination in combination with various different modalities. This is really where they have the most power in terms of future place in the treatment of GBM patients. Because one thing that we know that dendritic cell vaccination does is that it gets T-cells in the tumor, and although that’s sometimes not sufficient, it’s necessary. So that’s a necessary first step. Once the T-cells are in, there is, and I won’t go into that data today, but there is there is a micro-environment within glioblastomas that could actually deter an effective immune response, and that may have to do with checkpoint inhibition, some has to do with this population of immunosuppressive myeloid cells that come in, so there are different ways that we can modulate that with other agents, and that’s something we are looking at at UCLA, we’re looking at dendritic cell vaccination in combination with co-stimulatory molecules and checkpoint inhibitors. We are also looking at collaborations to look at CAR T cells in conjunction with DC vaccination and other types of protocols. This is just some preliminary unpublished data on our trial at UCLA whereby we are combining dendritic cell vaccination with PD-1 inhibition, and what we are showing is that…interestingly, when we give PD-1 inhibition neoadjuvantly – before vaccination – you actually get a survival curve that is better than just giving PD-1 alone, but if you give PD-1 inhibitor after dendritic cell vaccination you can boost that survival rate up to greater than 50%. Again this data is very preliminary, we are only half way through this trial so we don’t have final data yet but I think it’s encouraging in the fact that we probably can combine vaccine therapies with immune modulators to hopefully get a positive response for our GBM patients.
(Slide 26, 32:03) So with that I just wanted to thank all of the investigators that were involved in the Phase 3 clinical trial and all of the co-authors on this JAMA-Oncology paper that was published a couple weeks ago. It was really a wonderful group of people that I’ve worked with, and with that I will stop and take any questions.
This is great work and valuable DD, Senti, thank you!!!
I don't think it's either or -- timing and dosage could be fine tuned to include, for example, Murcidencel, Hiltonol, and Keytruda. Side effects would be a factor too. From what I can tell Hiltonol is mostly fatigue and rashes. Other might know more about this.
Thank you Senti for keeping the info section current -- we might feel like things are moving slowly but there's actually been a lot to update lately!
Lifespan WPRI News Conference, Jan 6, 2022 Transcript
https://www.youtube.com/watch?v=cU_-1ECBMAU
Video begins with Dr. Steven Toms, Dr. Heinrich Elinzano, and Dr. Wafik Aldiri at the dias
0:02
Dr. Elinzano: Good morning everybody, thanks for coming to this press conference. We called this press conference to share with the community this breakthrough study that came out a couple of months ago for which we were part of. It's a study on the most common malignant tumor that primarily involves the brain. It is called glioblastoma. Just to put things in perspective, glioblastoma has a survival of probably an average of one to two years – there's not a lot of good treatment options.
So this study came up with this treatment approach that really improved the outcome of these patients. To break down the results I'll simplify it. First off it improved the Overall Survival (OS) by several months compared to the standard treatment of radiation and oral chemotherapy. Two, it also almost doubled the proportion of patients surviving over five years which is a long time for this tumor. Then three, for those patients whose tumor came back, or recurred, it improved their survival more than twice what would be what we'd expect for someone whose tumor came back. It's also a novel approach, and Dr. Toms next to me will describe this design.
1:21
We used a vaccine approach in addition to the standard treatment, like I said, of radiation and oral chemotherapy and it's a big study. It included 94 sites, one of which is Rhode Island Hospital and Geisinger is the other, in about four countries. Studies like this are quite rare in this tumor because they're not too many of these tumors, although they are the most common malignant brain tumor, and conducting a study with different sites also has its own set of problems. I'd like to turn over now to Steve Toms who will describe the design of the study and then after him, I'll turn over to Dr. Aldiri to kind of give us an idea of where cancer care is heading in our state of Rhode Island.
Dr. Toms: Thank you Dr. Elinzano. I want to welcome everybody who's come to talk about this exciting development and, you know, highlight some of the local flavor of it. the lead investigator on this study was Linda Liau, she was class of ‘87 here at Brown and a year behind me. Her daughter is currently a student here at Brown, and Dr Liau is currently chairperson at UCLA. She’s been studying these immune techniques in cancer over about the last 35 years.
2:41
The study was designed initially as a randomized control study, which is the standard in cancer therapy, and a randomized trials – but unfortunately due to some changes in the care of glioblastoma of the 20 years and some design elements that the FDA mandated, including crossover such that the patients who did not get the vaccine up front got vaccine later on, the data is a little tough to interpret in some ways. As Dr. Elinzano pointed out, the data suggests about a three-month survival increase in the patients who got this vaccine in overall survival, but
the thing that really stood out in this was the tail – the number of long-term survivors.
In communications with Dr. Liau, she has a few patients who are 17 and 18 years out under this treatment, which is longer than any survivors I or Dr. Elinzano have. I have a couple of 12 year survivors at this point.
Let's talk a little bit about how this complex study went. So as Dr. Elinzano mentioned, the standard of care for glioblastoma is that, you know, a barber such as myself, a surgeon does a bad haircut, goes ahead and does an operation to try and take out the maximum safe amount of the tumor you can. In some patients it's as small as a needle biopsy because it's in such an eloquent area of the brain, but our goal is to try to have those surgeons such as myself get out as much as we can. Then we follow that typically with six months of radiation with concurrent oral chemotherapy, the temozolomide.
4:22
What made this study unique is that we took each of the patient’s cancers and we put those essentially on ice and shipped them down to a place for processing. The tumor samples are then processed by lysing the tumor cells, which exposes some of their proteins, including the
proteins that are on the cell surface. The body can then recognize and attack. These things are called neoantigens, or new proteins, that come out in the cancer during the cancer evolution. So once that is done the patient then had to undergo a special type of procedure called a leukapheresis where their blood is drawn out and monocytes, which are a type of immune cell in the body, are taken from the patient. Those are then again put on ice and shipped down to a processing center centrally in the U.S, turned in the petri dish to these specialized cells called dendritic cells. Dendritic cells are a type of immune system that's involved in that antigen processing which is taking proteins in the body, whether it's from a
bacteria, a virus, or new proteins from the cancer and processing them such that other immune cells can recognize and then attack them. So essentially what was done is in the petri dish or in the laboratory the lysate or the proteins from the tumor were then mixed with the patient's own immune cells, and those immune cells were processed the tumor themselves, and then were used to re-inject into the body as a vaccine.
Each of the injections included about two and a half million dendritic cells and they were done about three times the first month and then every other month for about six months up to a maximum of 10 to 12 vaccine inoculations. Each of those inoculations is very similar to the vaccines we're all familiar with for the flu and COVID and what not.
6:04
So where we are with this process right now is that the study is out and has been reported, the data is looking quite promising but as we said it is a little bit messy because we don't have an internal control because of changes that were mandated by the FDA. But there's
certainly signal there that I have seen myself. Dr. Elinzano, an oncologist who have been involved in this study has seen, and in fact Dr. Liau has been continuing to work on these processes and combining her vaccine with some things called immune checkpoint blockade that rev up the immune system as well and are used in many other cancers such as kidney cancer, and melanoma lung cancer very commonly. In early studies that she has done with 10 to 20 patients she is seeing some survivals of five years, up to 40 to 50% vs the 4 to 5% we used to see in our traditional treatments and the 13.5/14% we saw in this study of using the vaccine alone. So I think there's a lot more promise in this type of technique. It's the first personalized cellular therapy that's been designed for cancer and we're hoping that the FDA will act on this within the next year or so.
7:25
The thing that's important for all of our patients to remember is if they or a family member have someone with glioblastoma it is important to be seen at a specialized cancer center that deals with brain tumor. Here at Lifespan we have a multi-disciplinary brain tumor clinic; we'll have our brain tumor board, in fact, in this very room in about an hour where we meet weekly to go over complex cases and then every week we have our neuro-oncology team along with our radiation oncology team, social workers and our neurosurgeons all come together to see patients together to give Optimal Care. We hope and expect and certainly I advocate now that if you or a family member has glioblastoma you think about coming to a cancer center that will not only give you that type of treatment but have access to clinical trials, and I personally advocate for our patients to freeze their tumors at this point because if this becomes FDA approved there is a way where we can unfreeze the tumor and make the vaccine if we get to the point where we have this therapy available widespread in the next year or so for our patients.
So I I want to thank everyone for being here, to thank Dr. Elinzano for pioneering the study here. It's good to be back to the old alma mater. Yes?
8:36
Reporter: This is a quick question. Would you consider this a breakthrough?
Dr. Elinzano: I would. We would, I think. One, because right now, prior to this study there's probably just two standard treatments, with the oral chemotherapy and radiation therapy and there's a device that is approved for use for this type of tumor, but this vaccine approach is kind of a novel, a breakthrough in the sense that the results are pretty impressive compared to a standard that's already in use, it's a very innovative approach in managing this tumor.
Dr. Toms: I would echo what Dr. Elinzano is saying. In the in the past, since we had the improvements in early 2000s with what's called the Stupp protocol – combining the radiation and chemotherapy to improve survival from about 12 months to 14 months, we have not seen
much progress. There have been over 400 clinical trials in glioblastoma in that time and only two have been positive. One was for an electrical device called Tumor Treating Fields (TTF), which has increased survival somewhat and is relatively non-toxic, but patients find it hard to comply with that. This is a very easy protocol, has very limited toxicity that we've seen thus far – minimal immune reaction problems that we sometimes get with the immune checkpoint blockade drugs. So I think this is potentially a huge breakthrough for patients with glioblastoma and potentially with other solid cancers down the road once these techniques are applied to other cancers.
10:01
Dr. E: It's actually an important point which Dr. Toms highlighted, the quality of life aspect of it. Whenever you have a treatment approach you always want to balance out benefits you're deriving from the treatment and the risk or side effects that patients may experience with the treatment. In this particular study we didn't really see a lot of those. Although it wasn't highlighted in the study itself we have people who pretty much enjoy their day-to-day living without a lot of assistance with other folks and up to the point where their tumors sort of, progressed they were still kind of functioning as usual.
10:39
Reporter: How many people involved in the study?
Dr. E: So they're about 331 patients enrolled in the study, and so that included 94 sites, one of the sites is us here in Rhode Island. (inaudible question) It's done already, it's completed already and that's why it was published a couple of months ago.
Reporter: When did it start?
Dr. Toms: 2005/6, it was almost a 20-year long study.
Reporter: So that’s how you've been able to measure just how effective – you said some people still alive 12 year later?
Dr. Toms: Dr. Liau and some of her early studies, before this phase three trial, she's got some survivors who are 18 years out.
Reporter: This was Phase III? (nodding affirmative) So you expect, it is possible that the FDA could approve this within a year?
Dr. Toms: When I spoke to the CEO at our investigators meeting at Society for Neuro-Oncology (SNO) they said they are in the process of the application. They put together I believe she said three quarters of a million pages of documentation for the FDA thus far – it will obviously take some time to go through the application. but given that glioblastoma is in many ways an orphan disease with very few options. I feel like the 35 years I've spent doing research on this has been mostly an exercise in futility in that we've had so many failed trials. I get that even though the data is not perfect we would love that, you know, we had perfect data, but this is real world data. Given the mandates of the FDA that there was crossover and people were allowed to get the vaccine even if they were in the control group once they progressed because they had to undergo surgery, because they had to undergo an invasive procedure called leukapheresis, the FDA demanded that, the data is not as pristine as some would like. People have used that to try and tear down the data and say that this data is not effective, but I am somewhat biased as having been involved and having known the primary investigator since we were teens and knowing what a moral, wonderful person this is who's been doing this for years.
12:57
Reporter: The incidence rate for glioblastoma is what?
Dr. E: So the incidence rate according to the central brain tumor registry of the United States is about three per 100,000. We have a relatively high incidence here in Rhode Island so if you calculate about a million people in Rhode Island three per 100 000 that's probably about 30 cases per year but we see about 60 to 70 cases per year here in Rhode Island Hospital alone and that doesn't include other hospitals in Rhode Island.
Reporter: About 60 to 70 cases – why you think that's the case (next part of transcript not relevant to $NWBO)
14:35
Reporter: Which entity would be seeking FDA approval?
Dr. Toms: That would be the company that is trying to commercialize this, a company called Northwest Biotherapeutics and it's up to them to commercialize. They are a publicly traded company.
Reporter: Can you explain the difficulty in treating glioblastoma? It has these like little tentacles? So you can’t really get to everything and that’s why it tends to come back?
Dr. E: Exactly that's uh that's correct. As I often tell patients like plumbing a pudding that you just scoop out and be done with – there are microscopic cells left behind even if you're able to take out most if not the bulk of the tumor safely. And then we're dealing with a tumor that
involves the brain. The brain itself is a very delicate organ and so you encounter a lot of issues with treatment. And then there's still a number things unknown about this tumor, although we've come so far in terms of understanding the tumor, I think that there's still a lot of unknowns that we need to explore and do research on.
Host: Dr. Aldiri, would you like to provide a little bit of a comment and then afterwards we can just go to questions?
15:49
Dr. Aldiri: Thank you I'd like to thank everyone and in particular congratulate this amazing team for the tremendous progress that's been made in the treatment of brain tumors that's really affecting people's lives – this is very important for us in Rhode Island. (Non-relevant Rhode Island discussion)
18:09
Reporter: I have a question. If somebody comes in with a glioblastoma now do they have access to this vaccine or not until or if it is approved by the FDA? The clinical trials are done, right?
Dr. Toms: Correct the clinical trials are done. Right now the only access to this vaccine is through a Specials program in the United Kingdom, so unfortunately right now the only way to do it is to pay for it out of pocket, for us to take the tumor out and send the lysate over to the United Kingdom, have their leukapheresis done there, and the vaccine made there, and then the injections done there. So it's a very time and cost prohibitive thing. I believe the cost is somewhere near $200,000.
Reporter: So that’s why it’s so important to get it FDA approved…
Dr. E: Exactly. Yeah exactly. And it's not just an urgency because we need to take care of this tumor right away but really need to have options for them.
Reporter: Where is the funding coming from, where did the funding come from for the clinical trials and how much did that cost?
Dr. E: I don't know much about the exact amount but funding came from the sponsor which is Northwest Biotherapeutics.
19:20
Reporter: Did they get an NIH Grant or or anything like that?
Dr. Toms: So Dr. Liau has had multiple NIH grants to do her small studies at UCLA. She has had both R01 grants and what are called Spore grants and they have a small what's called a GMP facility at UCLA to make vaccine themselves. But they're an academic center, they can only make one or two vaccines per month and they cannot scale it. Northwest Biotherapeutics was the funding mechanism for this they've been a publicly traded company for many many
years.
Reporter: So when and where will the results of this come and be published?
Dr. E: They’re published already in November of last year in JAMA which is a big oncology journal.
Dr. Toms: Journal of the American Medical Association Oncology or JAMA oncology
Reporter: Really basic question. If the results were published in November why are you holding this news conference today?
Dr. E: Actually we wanted to do this much earlier on but there were a lot of issues. In December there was a weather issue that kind of affected the conference.
Reporter: So currently there are no vaccine treatments for glioblastoma?
Dr. E: There are vaccine treatments but they're investigational. So you may see clinical trials done by different centers, different approaches using vaccine or vaccine therapy, but none has been shown to be as effective as this one in a big large-scale study.
20:50
Reporter: This is an important thing? (nodding) You would regard it as a breakthrough?
Dr. Toms and E: Yes
(non-relevant Rhode Island research discussion)
I should have time this weekend to get that done. Before anyone sends me a note on this, yes, I know that Youtube has transcripts, so I'll be using that and just doing cleanup/formatting. Plus in this case I'll edit out the stuff that is unrelated to NWBO as they discuss at length local health issues.
Nice work Senti -- thank you!
Thanks Senti! I was just settling in to watch some football and do transcript cleanup and saw this. Very useful!
I will work on this over the next few days and will post unless someone beats me to it.
I posted that transcript on Dec 4 - post #543420