Edited: Now with JAMA podcast and LifeSpan transcripts
Well since some of you FUD lot obviously often need more than three years to actually comprehend what’s stated on NWBO matters, before it becomes knowledge, see it as a free service on my part, to keep you guys in the know.
Others know the webinar was taken down within one hour due to complaints and threats and only few saw the full video and most never saw the removed Q&A session, containing very positive information and Linda Liau confirming during said session that ATL-DC is DCVax-L.
You’re welcome!
The following is transcript of Linda Liau podcast for JAMA
The following is a transcript of the interview between Dr. Jack West and Dr. Linda Liau regarding the study "Autologous Tumor Lysate–Loaded Dendritic Cell Vaccination in Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial," published in JAMA Oncology.
Introduction and Context
Dr. West: Hello, this is Dr. Jack West from the City of Hope Comprehensive Cancer Center and web editor for JAMA Oncology, with another audio author podcast. I'm happy to be joined today by Dr. Linda Liau, MD, PhD, and MBA, who is the chair and a professor in the Department of Neurosurgery, as well as the director of the brain tumor program at the UCLA David Geffen School of Medicine. She's here now to discuss a new publication in JAMA Oncology for which she is the lead author: "Autologous Tumor Lysate–Loaded Dendritic Cell Vaccination in Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial." Thanks so much for joining today.
Dr. Liau: Thank you for having me.
Dr. West: So let's just start with some context. Can you please talk about this platform of autologous tumor lysate–loaded dendritic cell vaccination? What's the mechanism of action and what does it actually entail in practice?
Dr. Liau: Yes, so the mechanism of action for this platform really centers around the dendritic cell. Dendritic cells are professional antigen-presenting cells that are part of the repertoire of immune cells in the body. So the concept really is to take the antigen-presenting cells and present them to antigens. And particularly for brain cancer, dendritic cells don't normally circulate widely around the brain, so they may not recognize tumor antigens within the brain. So the concept is really taking a patient's own autologous dendritic cells and then pulsing them with antigens—and in this case, it is derived from the patient's own tumor tissue. So that is itself the vaccine, and then that's administered to patients.
And in previous preclinical and early clinical studies, we've found that when this is done, we can actually induce T-cell infiltration into glioblastomas, which is a way to make these non-immunogenic tumors immunogenic, because what we do know is that glioblastomas, unfortunately, do not have high infiltrations of T-cells. So this is a way to kind of induce that.
So that's essentially the mechanism of action behind this platform. And in terms of what this entails in actual practice, this is individualized or personalized immunotherapy in the sense that the dendritic cells are autologous, taken from the patient via leukapheresis, and the tumor tissue is also autologous, taken from the patient at the time of surgery.
And it would involve basically collecting the white blood cells and collecting the tumor cells, co-culturing them outside of the body at the manufacturing facility, and then when that product, that cellular product is made, that is shipped back to the individual sites for injection into the patients. And the injection is just a vaccine shot that's given in the arm, just like any other vaccination.
Trial Design and Endpoints
Dr. West: And the leukapheresis process and then all of the subsequent injections that are done initially every few days and then weeks and then maintained over months is all after the initial debulking or full craniotomy resection that gets the tumor tissue that's needed, as well as obviously being a therapeutic procedure. And then all of these patients underwent postoperative chemoradiation afterwards with temozolomide and per standard, both at that time and what would be done now, before going on to the vaccine. Is that correct?
Dr. Liau: Correct, yes.
Dr. West: Okay. So the trial itself, I believe, was developed as placebo-controlled and with an initial plan to have a primary endpoint of progression-free survival and comparing placebo to those who received the active drug or maybe vehicle compared to the active vaccine. It was converted to overall survival after the trial had been initiated. Can you talk about the process of the shift in the primary endpoint and why that came about?
Dr. Liau: Yes, so while the trial was underway, the field recognized that pseudo-progression is a major confounding factor in glioblastoma, particularly with newer immuno-oncology treatments and also in the MGMT methylated population, even with standard-of-care treatment.
So what happened as the trial was underway was that it became apparent that it was very difficult to distinguish what was true progression versus pseudo-progression. And the way the trial was designed, the determination of progression was actually made by independent radiologists at a centralized site. So all the trial sites would send in the MRI scans and the central radiology reviewers would adjudicate whether there was progression or not.
And what we began to find was that in over 50% of the cases, the radiologists did not agree. There was ambiguity in that adjudication. And then over the years in the field, what we've learned is that the way the radiological reviews are done does not really distinguish between progression and pseudo-progression.
This trial when it was written, the criteria that was used for that was based on the Macdonald criteria for determining progression, which is what was prevalent in the field at the time. Since then, that has been changed to the RANO criteria, the Response Assessment in Neuro-Oncology, but when immunotherapies came on board, that was viewed as not really adequate.
So there has been something called iRANO, but then iRANO lately was viewed as not adequate either, so now there's something called modified RANO. So anyway, through all of this, I think what we learned is that the field just still to this day cannot distinguish true progression from pseudo-progression. And that's why we changed the endpoint to overall survival, because that's at least a very non-equivocal endpoint.
Dr. West: And just to clarify for our listeners, I believe iRANO is for specifically immunotherapy with the potential for pseudo-progression, is that correct?
Dr. Liau: Correct, that is true. But just earlier this year, it was actually deemed that iRANO probably is not a good assessment criteria either, because part of iRANO requires a rescan in three months after initial visualization of tumor progression. And what was found when they applied this in actual practice is that almost 50% of the patients in immunotherapy trials then became censored. So all things considered, it still seems that, at least for our trial, overall survival was probably the best endpoint.
External Control and Results
Dr. West: And worth highlighting that the ultimate comparison was not internally as a randomization within the trial, but to externally controlled historical data from other trials. Can you talk about that decision?
Dr. Liau: Right, so the comparison to external controls was done based on the fact that we quite frankly lost our internal controls. There was a crossover arm designed into the trial and that was actually mandated by the FDA at the time because this was a relatively invasive procedure in the sense that patients had to undergo leukapheresis and surgery in order to enroll in this trial, so it was felt to be ethically best if patients were allowed the option of crossover if their tumor progressed. So with that and with the confounder of pseudo-progression versus true progression, what happened eventually was that almost 90% of the people in the control arm had crossed over. So essentially, there were very few people left in the internal controls and that's why the decision was made to compare this group of patients to external controls. And this decision was made prior to unblinding and it was written into the statistical analysis plan that was submitted.
Dr. West: Okay. So now let's get into the findings. What did you observe in terms of the overall survival for both the newly diagnosed and those with recurrent GBM cohorts compared to the external populations?
Dr. Liau: Right. So in the newly diagnosed cohort, what we found was that the median survival in our patients was 19.3 months compared to 16.5 months in the external cohort, when we compared it at the time of randomization, which the trials that were selected were all randomized at a similar time point.
And then in the recurrent cohort, that difference was 13.2 months in our vaccine-treated patients versus 7.8 months in the external cohort. But what I think was even more interesting is really the long survival tail in the vaccine cohorts. So the five-year survival in our trial was 13% versus 5.7% in the external cohort.
And interestingly, when we did subgroup analyses and parsed out the MGMT methylated patients, their median survival was almost three years. It was 30.2 months from randomization and 33 months from the time of surgery. And I find that actually very interesting because many of the immuno-oncology trials, for instance, the checkpoint inhibitor trials that have been done in recent years in the glioblastoma population, have purposely taken out the MGMT methylated patients because it was felt that this subgroup of patients with glioblastoma were responsive to chemotherapy, so we should be testing our immunotherapies in the unmethylated group. But what our trial showed was that perhaps the added survival advantage of immunotherapy could be more profound in the MGMT methylated subgroup. And this is something that would probably warrant further studies to validate, obviously.
Safety and Feasibility
Dr. West: What about the tolerability of the vaccine? Did you see any toxicity concerns in the clinic?
Dr. Liau: Surprisingly, no. We actually—there was actually very good tolerability for the vaccine and the safety profile was exceptionally benign. Out of the over 2,000 doses that were administered throughout the trial, we only saw five SAEs [serious adverse events] that were attributable to the vaccine itself. And most of the toxicities were relatively minor: flu-like symptoms, fever, fatigue, similar to what you would experience from any type of vaccination.
Dr. West: I didn't see numbers for the process of screening versus patients who were actually enrolled. Were there patients for whom the leukapheresis to obtain dendritic cells or the generation of the vaccine process externally from the tumor lysate was unsuccessful? How common was it for patients to get through from start to finish versus attrition along the way in real life?
Dr. Liau: So we actually did publish some data regarding the screening of these patients and the logistical issues related to vaccine manufacturing in a 2018 publication. But essentially, the percentage of patients who had screen failures based on unsuccessful manufacturing of the vaccine was about 6%. So there were some patients for whom we were not able to make vaccine work, but overall it was a relatively low percentage.
Clinical Implications and Future Work
Dr. West: Obviously, these data are favorable compared to the external data, but this study started more than a decade ago. Obviously, it's undergone some evolution. In that time, the field has evolved so that today, tumor treating fields [TTFields] would now be incorporated as a standard of care. That said, I understand that that can be cumbersome, it's not practiced that universally, but what would you consider the actual current clinical implications of this work to be given that the external data don't include tumor treating fields and that standard of care has at least optimally evolved somewhat since the conceptualization of this trial?
Dr. Liau: Yeah, that's a very good point. The trial that we conducted, as well as the external controls to which the trial was compared, did not include patients who underwent tumor treating fields. So obviously, that's a little bit different than currently.
But even with that being said, tumor treating fields is still not necessarily widely used in most of the larger academic centers. And I think the results of our trial in context to the current field—it really hopefully will allow further studies in the immuno-oncology space. I don't think the mechanism of action between dendritic cell vaccination and tumor treating fields are absolutely similar. So I think the reality is that we probably don't have enough treatments for our patients, not that we have too many. And different subgroups of patients will probably respond differently to different treatments.
So I think the goal in the future is to really decipher which patients may respond better to immunotherapies and vaccines and which patients may respond better to the tumor treating fields, and/or which may respond to both used concurrently. So I think this hopefully will serve as a platform for future studies of various types of combinations.
Dr. West: So essentially, this could be kind of orthogonal to tumor treating fields. I mean, they could be combined or approached independently. There's no reason that it has to be some either-or approach, but potentially a both-and. Yes?
Dr. Liau: Yes, correct. So I don't think it's necessarily going to be that we would need to prove that this is better or worse than tumor treating fields. It very well could be orthogonal or even complementary.
And as a neuroscientist, I think scientifically what is interesting about this approach is that what we do know is that it gets T-cells into the glioblastomas. And that could be what is needed. The activation of T-cells is needed to actually allow for other treatments such as the immunomodulators and the checkpoint inhibitors to really have an effect in glioblastomas, because those treatments have been effective in other cancers, but unfortunately, as single agents, we haven't seen efficacy in patients with glioblastoma. So hopefully, this will allow a window for that type of study to occur.
Dr. West: Do you see the next step of this being focused on the MGMT methylated subpopulation only or more broadly?
Dr. Liau: I think it would be focused more broadly and more narrowly. I think the answer is both. I think there is some efficacy in the unmethylated group as well; we're just not seeing the impact quite as great as in the methylated group. So I think MGMT methylation is probably a surrogate for some other biomarker that we have yet to discover.
Dr. West: Finally, we already alluded to the data supporting tumor treating fields, but the kind of underutilization in practice because of it being challenging, somewhat cumbersome in the real world, or at least in certain areas being underutilized. How does this potentially fit in? I did note that it's taken a long time, many years to enroll. It was from 94 centers to get over 300 patients. So is this something that could be adopted far and wide, or is this something that's really best suited for very specialized centers?
Dr. Liau: Because the trial was done in 94 centers around the world, many of these centers were not necessarily big academic centers; some were community hospitals. So I think that the completion of this trial showed was that this is feasible to be done at various types of centers throughout the world. What it involves is actually, like I mentioned earlier, collecting the tumor tissue at the time of surgery and the leukapheresis procedure and the manufacturing. But once that is done, the cumbersomeness on the patient is actually quite minimal. It just involves that the patient comes back for vaccine injections.
So I think just getting this trial done was quite a feat, but the fact that we were able to complete it, I think showed that it is feasible to have this vaccine manufactured at 94 centers. And on the patient side, hopefully it'll be well-tolerated and feasible.
Dr. West: Excellent. Well, Dr. Liau, congratulations to you and your colleagues on this paper, especially it being a field in which real advances are hard to come by and it's hard to show clinically meaningful progress. So really a valuable lead here. Great work.
Dr. Liau: Well, thank you very much.
The following is a verbatim transcript of the press conference held at Rhode Island Hospital regarding the Phase III clinical trial results for the DCVax-L glioblastoma vaccine, featuring Dr. Steve Toms (Clinical Director of Neurosurgical Oncology at Lifespan) and other medical experts.
Speaker 1 (Moderator/Dr. Al-Azzawi): Well, good morning everyone. Thanks so much 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 a part of. It’s a study on the most common malignant tumor that primarily involves the brain; it’s 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, and so this study came out 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 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. And then three, for those patients whose tumor came back or recurred, it improved their survival more than twice what we would expect for someone whose tumor came back.
It’s also a novel approach, and Dr. Toms next to me will describe this design. 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 there’re not too many of these tumors, although they’re the most common malignant brain tumor, and conducting a study with different sites also has its own set of problems.
So, I’d like to turn over to Steve Toms, who will describe the design of this 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. Steve Toms: Thank you, Dr. Alonzato. I want to welcome everybody who’s come to talk about this exciting development and highlight a little bit 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’s currently a student here at Brown. Dr. Liau is currently Chairperson at UCLA, and she’s been studying these immune techniques in cancer over about the last 35 years.
The study was designed initially as a randomized control study, which is the standard in cancer therapy and randomized trials, but unfortunately due to some changes in the care of glioblastoma over the 20 years and some design elements that the FDA mandated—including crossover such that the patients who did not get the vaccine upfront got vaccine later on—the data is a little tough to interpret in some ways.
As Dr. Alonzato 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. Alonzato have; I have a couple of 12-year survivors at this point.
And you know, let’s talk a little bit about how this complex study went. So, as Dr. Alonzato mentioned, the standard of care for glioblastoma is that 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 the surgeon such as myself get out as much as we can. And then we follow that typically with six months of radiation with concurrent oral chemotherapy, the temozolomide. What made this study unique is that we took each of the patients’ 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 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 US, 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 reinject into the body as a vaccine. Each of the injections included about 2.5 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. And each of those inoculations very similar to the vaccines we’re all familiar with for the flu and Covid and whatnot.
Where we are with this process right now is that the study is out and has been reported, and while the data is looking quite promising, it is a little bit messy because we do not have an internal control due to changes that were mandated by the FDA. There is certainly a signal there that I have seen myself; Dr. Ellenzato, an oncologist who has been involved in this study, has seen it, and in fact, Dr. Linda Liau has been continuing to work on these processes and combining her vaccine with treatments called immune checkpoint blockades. These treatments rev up the immune system as well and are used very commonly 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 percent versus the four to five percent we used to see in our traditional treatments and the 13.5 to 14 percent 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. 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. And 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.
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