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Remember that once they enrolled patients that both PFS and OS was out of their hands. All 331 patients were screened (meaning surgery occurred) before the August 2015 halt. By this summer all 331 patients will be 2 years out from surgery. Most of the 331 patients are already 2+ years out from surgery. In fact, from my estimation in the next week we will have approximately 267 patients who were enrolled for 2 years already. Those 267 patients are at least 27 months out from surgery. And 248 are about 30 months out from surgery soon. I think that reaching OS could come at any time, but yeah, I'm leaning that this trial will run until sometime Q3 this year, when all 331 patients will be no less than 2 years out from surgery. I'm expecting the placebo Median be closer to 27 and the vaccine closer to 36 months. Not all the placebo patients will see a longer survival because of DCvax, but I do expect those that get a second resection may end up seeing a longer PFS2 than they did their PFS. The longer this goes into summer, the more confident I'll feel. :)
By Quarter ending date/year: Enrollment cumulative #)//cumulative randomization (placebo:vaccine)
Q3 2008: 11 patients (3:8)
Q3 2011: 15 patients (5:10)
Q4 2011: 23 patients (8:15)
Q1 2012: 35 patients (12:23)
Q2 2012: 49 patients (16:33)
Q3 2012: 63 patient (21/42)
Q4 2012: 83 patients (28/55)
Q1 2013: 103 patients (34/69)
Q2 2013: 125 patients (41:84)
Q3 2013: 147 patients (49:98)
Q4 2013: 169 patients (56:113)
-- 66 patient IA event, old SAP
Q1 2014: 187 patients (62:125)
Q2 2014: 205 patients (68:137)
Q3 2014: 223 Patients (74:149)
Q4 2014: 245 patients (81:164)
Q1 2015: 267 patients (89:178)
Q2 2015: 295 patient (99:196)
Q3 2015: 331 patients (111:220)
You are correct.
From Security Analysis best seller:
A daunting challenge.
If Graham and Dodd so widely read and respected, why there's so few discipline practitioners of device? I believe that answer lies in three human traits: aversion to boredom, a tendency for emotions to overwhelm reason, and greed.
Careful research takes time and sold them results in a clear case for buying a large position. It is tedious to review company if the company only to find that most are neither really special know greatly undervalued. Equally tedious the whole shares in good company for an extended period of time. Even if the investment does well, most of the time it feels like the stock is treading water were even going down. Part of the problem is that the value of the business is quoted 6 1/2 hours a day, five days a week, 52 weeks a year, and market liquidy tempts us to trade from one stock to another.
The second challenge is rattling best thing is to maintain one's logical conviction in the face of excessive gloom will euphoria as reflected in the stock prices. I doubt many owners of private companies are preoccupied with the value of the business on the short-term basis-how different from the public markets, where rising stock price makes us feel smart and falling one makes us feel dumb. In my office, and one of her business is floundering and the stock is getting pounder, my partners and I start to doubt the reason basis upon which we made the investment. Her self doubt and fear is a failure call just to glimpse catastrophe or once we envisioned opportunity. Or if you prefer Graham and Dodd condensed version: "Obviously require strength of character in order to think and act in opposite fashion from the crowd and also patience to wait for opportunity that may be spaced years apart."
The third factor, greed has always distorted investors behavior, but it is especially present in the markets today given the proliferation of hedge funds. Investors and response keep jumping from fund to fund, trying to latch onto the latest hot manager. The high please encourage these managers to pursue "get-rich-quick" trading strategies. The more money they make, the more money they track, and the investors have been sold and the promise of unsustainable high returns. A cycle ensues as hedge funds investors quickly move the money from fund to fund, and head to manager try to swing for the fences every month. I once attended to U.S. Open set me up to hedge fund managers I did not know. They were talking shop during the match, and much to my surprise, their discussion focused exclusively on assets under management and fees. I kept waiting for them to mention and that's when idea, but it never happened.
Today the crowd focuses on isolated data points. The latest wiggles in the business outlook, or the opinion expressed in the most recent research report. With so much information available, there is a tendency to act quickly to buy and sell in haste, and to substitute the views of others for the hard work necessary to come to one's own conclusion. Perhaps this is why so many market participants can be described only as "Traders" and "speculators," unafraid of using debt to turbocharge returns. Their methods require frequent profitable traits, after transaction costs, and car for higher taxes then the long-term investor pays. We also pay heavy price and terms of emotional wearing tear. It is easy to vacation enjoy family if one owns a great business-and it is impossible if one is tracking a flock of trading positions about which one has little conviction. Most importantly, a fast-moving, leveraged approach is likely to fail spectacularly at some point over a lifetime, which is unacceptable risk for those of us who invest our own money alongside our clients.
If you investors the station to take the time to truly understand the quality and the motivation of top management. This book clearly emphasizes the importance of unflinching intellectually honesty on the part of an investor will prepare an analysis-match by similar integrity in the management of the enterprise in which the investor places client capital. Slick managers, who always have an infallible Business plan and dismiss all past mistakes as nonrecurring anomalies, will do everything they can to prevent you from peering behind on Oz's curtain to see the true outlook for their business.
A recurring theme of security analysis is the importance of gathering as much information as possible, but the making judgments, which are subject to being widely off the mark. One will not find any claims of the "surefire" way to pick stocks. There is recognition that even the most exhausted analysis can fail to bring the investment success. Graham and Dodd don't make security analysis seen easy or guarantee your profit. During my Nisha weeding of the book many years ago, I wish I digested I wish I had digested the short preface to the first edition: "we are concerned chiefly with the concepts, methods, standards, principles and, above all, with logical reasoning." The authors were not trying to write "investing for dummies" or chronicle of stock tips. They were trying to help the thoughtful investor develop a successful approach to long-term wealth creation "which Will stand the test of that ever enigmatic future." I have come to believe that it may require a bit of experience on the part of the reader to fully appreciate the power of this book to remain relevant. Perhaps the wisdom, like youth, is wasted on the young.
Another fascinating Alameda part for his discussion of optimal capital structure, because it speaks to the current media frenzy over private equity investors. First problem in the 1980s and more dramatically today, investment groups have applied leverage in order to enhance equity returns in taking companies private. This book refers to such levered, option-like-equity holders as having a situation in which "heads I win, tails you lose." This seems particularly for the Gen. partners of today's private equity firms. Indeed, high leverage can lead to outsize returns, but it is another form of speculation, much like buying stock at a very high P/E ratio.
I will presume a little too imagine how the authors would analyze the likely investment return for those limited partners only now allocating huge sum of money to private equity megafunds. Pioneering institutional investors in a private equity fund lazy alternative investment trail 20 years ago. Now that Yale's investment approach and success are widely celebrated, salmon and state retirement fund managers want to join a party that is close to ending. By our prices have never been higher, strategic buyers are regularly outbid by ravenous Financial buyers, and remaining opportunities for operational improvements are few. expected returns, in short, or German almost solely by maximizing leverage. With many biopsies less priced unlevered for our clear skies and smooth waters, the general rise in interest rates for business downturn could be disastrous. The equity In these deals-that is, the limited partners capital-could easily be wiped out. One wonders if the stewards of capital pouring money into private equity today have any concept of the risk they are taking as fiduciaries. Interestingly, the private equity firms himself are going public a generous valuations even though they have a little permanent business capital, the lifeblood of the businesses. What if they're limited partners are not satisfied with the results and don't re-up? What's the correct PE for business model that's facing the risk of destruction? Investment in these companies would seem very embodiment of the term "speculation."
Similarly, but with the authors make up today's collateral debt obligation that have been bought, not based on due diligence but on the AAA rubberstamp from the credit rating agency? For lenders rushing to scoop up "covenant-light," "pay-in-kind" won't use the 90%-levered capital structures? Institutional appetite for hedge funds and "2-and-20" fees? Investment thesis built around ever-rising valuations and continued "global liquidity"? There's no need to wonder-Security Analysis, timely as ever as much to say on speculative excess.
Yes, we have heard the speech before: the stock market is a voting machine, not a weighing machine. Future prices fall outside the realm of sound prediction. Even the best companies can be speculations at the wrong price. One must understand the nature of the business to assess the inheritance permanence of earning power. Well it's easy to say, it is hard to actually "buy low and sell high" because human nature program plus to take comfort in the company of others. This is distinction between investing and speculation. Never in the ass with unscrupulous management. Earnings must be understood in the absence of nonrecurring items. Debt in the capital structure enhances returns but there are limits. The market sheets first and finds reasons later.
If it is all self-evident, like Polonius's speech, that's because touch with them I stood the test of time is become part of our lexicon of investors. If you people endeavor to walk the walk by researching business intensively shifting through many dozens to find a worthy of their capital. Few people are willing to concentrate their investments in a small number of businesses that they know thoroughly unbelievable bro they're not worth any attractive rate over the long-term. Many days this work is just plain boring. Other days (and sometimes months), The market totally ignores your handful of precious stocks. Fully a predictable, reliable businesses does not make you the most exciting person at the cocktail party, nor does it give you flashy sales promotion material. I've come to believe the quest for rational investing is appealing only to a handful of us. But at least we sleep well at night and live well by day-and our clients do well.
Synergies with Bevacizamub, I imagine. Here's a very interesting cell discovery paper.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045963/#!po=0.892857
Folks who are betting against the company and the stock price, want us to judge the company badly over the fact that the trial remains blinded and on-going. The longer the study remains blinded is good for patient survival as it means 233 OS events have not been reached. This is a good thing, which even Linda Liau vocalized. The skeptics want us to ignore this. We already know that 10 of the Compassionate Use Arm patients remain alive over 5 years. There are very few GBM patients alive over 5 years. They want us to ignore that too. Confidence over the company stock may be circling the drain right now, but that doesn't mean it's appropriate to perceive that it has any correlation to the science. The company did a capital raise. That's unfortunately both a negative and a positive. The good news is they will survive another day, with the likelihood of getting to the end of the study rising. The bad news is that without scientific news to bring new buyers it may end up being that the stock continues to be volatile and potentially trends to test lower support. The science reveal will ultimately determine where this stock should head as this limbo land of capital raises without abstract updates have been destroying shareholders value. In the end the number of outstanding shares will affect how high this stock can go assuming success. The share count can continue to climb, but I do think that there is a chance that they may not need to raise again before Phase III news. But Turtle is correct, there's also a chance that they may need to raise again in a few months. The longer this goes the better the science may be, but unfortunately it may mean that those last in benefit most. That's one of the things that bothers me most about the company silence. But I do get that it's best for them not to promote the stock. They can't handle another lawsuit distraction. I'm patiently waiting for the study to end. Endpoint news can't be refuted.
Here's a very interesting study. Notice the two scans are used. And also notice the MEAN for Chemotherapy and OS.
https://academic.oup.com/neuro-oncology/article/19/suppl_1/i17/3059798/PP62-DO-THE-RESPONSE-ASSESSMENTS-ON-MRI-SCAN?searchresult=1
The U.K. Investigators wouldn't be so fascinated with TIL if it didn't correlate to OS. This abstract release is days old.
PP72. IMMUNE INFILTRATION OF TUMOR MICROENVIRONMENT FOLLOWING IMMUNOTHERAPY FOR GLIOBLASTOMA MULTIFORME
Mr Giannis Sokratous Mr Stavros Polyzoidis Prof Keyoumars Ashkan
Neuro Oncol (2017) 19 (suppl_1): i20. DOI: https://doi.org/10.1093/neuonc/now293.072
Published: 02 March 2017
Abstract
BACKGROUND: Autologous dendritic cell immunotherapy has been proven effective in treating tumours outside the central nervous system. Current evidence from phase I and II trials suggest a similar efficacy for central nervous system tumours as well and that an active immune response against these tumours can be generated. OBJECTIVE: We aim to review the literature to identify the types of immune responses against gliomas found to be generated by dendritic cell vaccinations and the types of immune cells subsequently infiltrating the glioma microenvironment. METHODS: A systematic review of the literature was performed by searching the online databases PubMEd, Google Scholar, and EMBASE with use of the keywords intratumoral, infiltration, lymphocytic, vaccination and gliomas. RESULTS: Seven studies reporting lymphocytic infiltration of gliomas microenvironment were identified. Three studies (42.8%) reported presence of tumour infiltrating lymphocytes in 50%, 50% and 28.6% of included patients respectively in the post-vaccination specimens that were not present in the pre-vaccination samples. The remaining 4 (57.2%) reported an up to six-fold increase in the number of pre-existing lymphocytes following vaccination. CONCLUSION: Present data indicate that tumour infiltration by lymphocytes can be induced by dendritic cell immunotherapy and that this may positively affect clinical outcome. It still remains unclear which factors influence the above reaction and therefore prediction of response to treatment is still not possible.
Same authors wrote this:
Human Vaccines & Immunotherapeutics
DCVax®-L—Developed by Northwest Biotherapeutics
Stavros Polyzoidis* and Keyoumars Ashkan
Department of Neurosurgery; King’s College Hospital; King’s College; London, UK
"Current standard of care for ND-GBM is set by the landmark “Stupp” protocol.2 This was introduced in 2005 and consists of a six-week regimen of concomitant radiotherapy and temozolomide chemotherapy followed by a six-month course of adjuvant temozolomide administered over six 28-day cycles, during which the patient is given temozolomide for five consecutive days per cycle. Even with the application of this optimized protocol combined with radical surgery mean OS is 14.6 months, two-year survival (2-YR S) is 26.5% and only »3% of patients survive longer than five years.5,6"
Conclusion:
The lack of significant improvement in the prognosis of patients with GBM in the recent years warrants exploration of new therapeutic avenues. DCVax-L as an autologous active DC- immunotherapy agent has achieved promising outcomes with little side effects in phase I/II trials. The ongoing phase III trial is aimed at verifying these preliminary results, which if achieved, will have a major impact in the management of patients with GBM.
http://www.tandfonline.com/doi/pdf/10.4161/hv.29276
Abstract from U.K. DCVax-L Investigators:
PP72. IMMUNE INFILTRATION OF TUMOR MICROENVIRONMENT FOLLOWING IMMUNOTHERAPY FOR GLIOBLASTOMA MULTIFORME
Mr Giannis Sokratous Mr Stavros Polyzoidis Prof Keyoumars Ashkan
Neuro Oncol (2017) 19 (suppl_1): i20. DOI: https://doi.org/10.1093/neuonc/now293.072
Published: 02 March 2017
Abstract
BACKGROUND: Autologous dendritic cell immunotherapy has been proven effective in treating tumours outside the central nervous system. Current evidence from phase I and II trials suggest a similar efficacy for central nervous system tumours as well and that an active immune response against these tumours can be generated.
OBJECTIVE: We aim to review the literature to identify the types of immune responses against gliomas found to be generated by dendritic cell vaccinations and the types of immune cells subsequently infiltrating the glioma microenvironment.
METHODS: A systematic review of the literature was performed by searching the online databases PubMEd, Google Scholar, and EMBASE with use of the keywords intratumoral, infiltration, lymphocytic, vaccination and gliomas.
RESULTS: Seven studies reporting lymphocytic infiltration of gliomas microenvironment were identified. Three studies (42.8%) reported presence of tumour infiltrating lymphocytes in 50%, 50% and 28.6% of included patients respectively in the post-vaccination specimens that were not present in the pre-vaccination samples. The remaining 4 (57.2%) reported an up to six-fold increase in the number of pre-existing lymphocytes following vaccination.
CONCLUSION: Present data indicate that tumour infiltration by lymphocytes can be induced by dendritic cell immunotherapy and that this may positively affect clinical outcome. It still remains unclear which factors influence the above reaction and therefore prediction of response to treatment is still not possible.
I've said for many years that the Company might treat PFS as an interim and that they would DEFINITELY keep the trial blinded until OS. I stated this well before any skeptic came along and repeated it. I was alone in my assumption for a very long time on the fact that the company would not dare to unblind the trial before OS was reached.
The only reason I thought they would data lock PFS is because their December 2016 PR gave the impression they would. But if data locking PFS meant unblinding before OS triggered then there was no way that I thought they would do that. I honestly think they could have data locked PFS and simply kept OS blinded. I suspect it has part to do with money as it's costly to repeat the data lock process twice.
The skeptics want to pretend PFS hit well before it did. What they fail to account for is that we are still without an OS event. If PFS endpoint, of 248 patient events, hit in the timeframe of their creative imaginations, then majority of those events would have turned over to OS events. It isn't as if PFS events stop, new ones get added. And that means a bigger pool of PFS crossover patients to turnover into OS events. By skeptics calculation, we'd likely be closer to 300 PFS event by now. If this were a placebo only study, then we wouldn't be a year out from OS primary event crossing. Almost all first recurrent patients die. That's a fact. This isn't a disease where PFS never materializes into changing into an event. Again, almost 100% of PFS change into a OS event. And it wouldn't be that all the 248 events hit the same month regardless of who models events. Obviously a bunch would have hit years earlier, as this trial has been on-going since 2008. Yet we are supposedly over a year out from when they say PFS hit, and still waiting for OS. That makes no sense and they know it. Two hundred and forty-eight and counting Patients don't live a year after their PFS events regardless of the salvage therapy. They can say whatever they want. It's just noise that we have to tune out until the data is revealed.
NW Bio's tissue bank service is Health Bank. It's not NWBio Trust.
https://www.nwbiotrust.org/en.html
http://uwtv.org/series/laboratory-medicine-grand-rounds-2013/watch/zslccWCMhzo/
He was first treated at MD Anderson in Houston. And then when it returned at Walter Reed National Military Medical Center in Bethesda.
https://www.fredhutch.org/en/news/center-news/2015/06/beau-biden-treating-brain-cancer.html
Abeta, that's fine. Thanks for letting me know.
I had sold out near the top China. The history is on the iHub why. The history is also there as to why I bought back in. I actually bought most of my shares well under $1. Very few over $1. As a reminder, I sold my $2 shares when it was clear to me it wouldn't recover over the 300 million
Market cap. I opted instead to buy far out options, which I lost some of my profits. And when it fell below $1 I added. I also added when it fell lower and then sold out my higher share cost on a rise, replacing with my lower cost ones which I opted to keep.
I'm doing more than fine China. I'm sure I'll retire young. Thanks for your concern.
To be clear China, I'm obviously down on my NWBO holding. But, I have no intention to sell my shares. Given that I did sell my shares years ago; I still think I'm in profit territory if I had wanted to walk away. I don't plan to. I've done my due diligence.
I'm not in the least bit worried. If anyone asked me last summer if this could go to $.10 or less before news, I'm pretty sure that they would say that I was VERY clear that it could. No one knows the bottom price this will reach. No one knows how many shares there will be in the end. It is hopefully clear that upper resistance will not come down without incredible positive news. It should also be very clear that the company is not making any attempt to inflate the stock price with survival updates and the "positive" like. They don't want to be sued by more shareholders for encouraging anyone to buy shares at this point and so in my opinion they won't release news that can be manipulated to be perceived as false "positive". And so, that leaves us with the obvious, the price won't go up unless something that can't be refuted comes in. The scientific community consensus and study outcome eventually is either going to save the company stock price or it isn't. And obviously I'm will to watch the share price volatility as I perceive that the vaccine will garner some type of approval ( if not all GTR patients -- perhaps the Mesenchymal biomarker and pseudo biomarker). It isn't the day to day stock price that counts. It's the pending study start(s), the preliminary findings and Phase III endpoint news day that counts. I won't say exactly when I plan to add. But I do plan to add eventually as I believe the outcome I expect with the science will occur in due time. My old shares were diluted (current cost stagnant at $.42) but it was a risk that I understood, and was willing to take with a small percentage of my money. It was a risk that I vocalized to longs, urging caution, suggesting folks invest slowly and stay diversify. And it was advice that I myself followed. I'm not in the least bit concerned over price. I'm going to be fine whatever happens. I hope the same for all longs.
Yup. We have no idea how many shares will be issued by the time study news comes in, but it does appear they averted bankruptcy. Hard to figure out how many shares we are at now exactly. It just sucks that they had to raise so low but at least they raised a decent amount. A few more months and hopefully we will know the outcome. GL to all shareholders.
Hi Turtle, I hope all is well. I haven't seen any recent buys or sells from her holdings; think it's okay to assume her count hasn't changed. Time will tell if it's accurate. Best, RK
I'm sure you're aware that this isn't DCVax-L. But I sent it to you as it is yet another study that shows impressive PFS and OS of an intent of GTR patients on an dendritic cell (DC) vaccine.
Your post was survival data of older patients on Chemotherapy with extended adjuvant TMZ. The DC study data on those 5 older patients came from a larger study pasted near the bottom of this post. The immunotherapy trial enrolled 31 of 32 screened. FG surgery is commonly used today, particularly at clinical sites that do not have iMRI suites. There was no selection bias other than a less than 1 cm2 residual tumor for study entry. Patients were enrolled from the time of FG surgery specifically to avoid selection bias. From the nomograms, each patient was assigned an expected life expectancy based on their individual respective circumstances. Majority of patients lived longer than their Standard of Care expectancy, per the quote : "Compared to EORTC nomograms, 23 patients have lived longer than predicted, 3 have lived shorter, and 5 do not have enough follow-up information (p < 0.001, binomial distribution). "
It is my understand that "un" methylation MGMT was not a negative factor, but that doesn't mean all patients were able to overcome their dismal prognosis. I do not know how long patient #2 was meant to live. But it was impressive that the 5 older patients seemed to benefit from the synergies of Dendritic Cell immunotherapy with other therapies (RT, TMZ and Bevacizumab). These are older patients who typically do not live over 2 years, and yet 4 out of the 5 did.
As for the Patient #2 you referenced, he was a 73 year old male, had early progression disease which was confirmed by a second scan (back dating the PFS event; bevaciaumab did not begin until true TUMOR progression was confirmed). The patient had delayed vaccine administration, received a total of 4 injections. He had a seizure a month after surgery and toxicity to chemotherapy, but was an MGMT unmethylation patient. He survived 9 months. But he may have been considered a partial response. Had he not had four injections he may have done worse. What is also interesting is that they may were not able to use the "invasive" part of his TUMOR tissue for the vaccine. That may have made a difference. As for your reference of the "secret sauce", I have long felt that not all lysate tissue is equal, and there are some parts of TUMOR removed that has more TUMOR cells than others. The antigens used for presentation are just as important as the method used D.C. maturation IMO.
"From three patients (UPN 1, 4 and 5), we separately received material from both central and invasive portions of the tumor. Both tumor components were used for vaccine production in all three cases. In the remaining two cases, only material from the central portion was obtained."
Also notice that "Psuedoprogression" was ruled out as for the reason for the early MRI reading. Scans of non-progression patients did not get progressively worse. Only patients who fit the description of two consecutive MRIs had back-date progression at 3 months.
"Progression-free and overall survival :
All patients have progressed, with a median progression-free survival (PFS) from surgery of 16.1 mo (range: 3.1-20.3). Only one patient was re-operated at recurrence. UPN 2 and 3 had already early radiological progression signs at the time of the first vaccination. In both patients, bevacizumab was started after a second MRI indicated that these signs were not suggestive of pseudo-progression. UPN 2 had a partial response before further progression and death. UPN 3 had a total response to bevacizumab."
This was the vaccine schedule:
"First DC administration was scheduled prior to radiotherapy, second one, three weeks after radiotherapy, followed by two monthly, four by-monthly, and later quarterly until the end of all available doses."
"Five patients were screened and included (Table ).1). Mean age was 66 years, median KPS was 70, four patients were RPA class V and one was class IV. MGMT promoter was unmethylated in one and methylated in four cases. Mean preoperative tumor volume was 54 cc (34-112)"
Here is the patient specific data:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536842/table/T1/
And the larger study:
IMMUNOTHERAPY WITH TUMOR LYSATE-PULSED DENDRITIC CELLS FOR NEWLY-DIAGNOSED GLIOBLASTOMA FOLLOWING FLUORESCENCE-GUIDED RESECTION
IT-03. IMMUNOTHERAPY WITH TUMOR LYSATE-PULSED DENDRITIC CELLS FOR NEWLY-DIAGNOSED GLIOBLASTOMA FOLLOWING FLUORESCENCE-GUIDED RESECTION
Ricardo Diez Valle,1 Sonia Tejada,1 Suana Inogés,1 Miguel Angel Idoate,1 Ascensión Lopez Diaz de Cerio,2 Jaime Espinos,1 Javier Aristu,1 Jaime Gallego,1 Javier Perez Calvo,1 and Maurizio Bendandi1
BACKGROUND: Immunotherapy is a promising therapy for glioblastoma, however, different strategies and potential selection biases make it difficult to evaluate efficacy. We hypothesized that treatment with tumor lysate-pulsed autologous dendritic cells would be effective when added to gross total resection and standard radio-chemotherapy in newly diagnosed glioblastoma. We designed a trial recruiting patients from the time of surgery to avoid selection biases.
METHODS: All patient candidates for resection during the study period were screened, and an attempt at maximum resection was made in every case using fluorescence-guided surgery; less than 1 cm2 residual tumor and glioblastoma pathology were required for entry confirmation. Adjuvant treatment included radio-chemotherapy with temozolomide up to 12 cycles. Vaccines were prepared as soon as possible after surgery using autologous dendritic cells pulsed with tumor lysate and matured ex vivo. The vaccination calendar started before radiotherapy. Overall survival was compared to a historic cohort and to European Organization for Research and Treatment of Cancer (EORTC)-published nomograms.
RESULTS: We screened 32 patients and included 31 (96.9%); one was excluded because of the presence of residual tumor. The mean age was 58.6, and Karnofsky performance status score was 90-100 in 28% of the patients, 70-80 in 65%, and 60 in 6%; 10% of the patients were in RPA III, 42% RPA IV, and 48% RPA V. Immunotherapy was well tolerated and induced specific immune responses. Median overall survival at the moment of this writing is 27.4 months versus 14.7 months in patients treated with the control (p = 0.003). Median survival in RPA class V patients is 26.9 versus 10.7 (p = 0.007). Compared to EORTC nomograms, 23 patients have lived longer than predicted, 3 have lived shorter, and 5 do not have enough follow-up information (p < 0.001, binomial distribution). In multivariate analysis, vaccination was the most significant variable (p = 0.012, odds ratio 2.7; 95% confidence interval: 1.24-5.77).
CONCLUSION: Tumor lysate-pulsed, autologous dendritic cell vaccination is safe and effective when added to standard therapy after gross total resection in glioblastoma.
And here is rates on FGS:
http://www.ncbi.nlm.nih.gov/pubmed/20607351/
Soligenix to Present Data on Dusquetide in Combating Antibiotic-Resistant ...
http://www.prnewswire.com/news-releases/soligenix-to-present-data-on-dusquetide-in-combating-antibiotic-resistant-infections-at-the-19th-annual-superbugs--superdrugs-conference-300423383.html
Vastly different than what might be possible for elderly patients who respond to immunotherapy. I've posted this before, but it seems timely to post again given the topic.
***
Dendritic cell vaccination in glioblastoma after fluorescence-guided resection
INTRODUCTION
The prognosis of glioblastoma multiforme (GBM) remains dismal[1]. Radio-chemotherapy’s benefit has been recently proven (14.6 vs 12.1 mo; P < 0.0001), but overall survival (OS) is still short, only 26% of the patients surviving two years[2]. Targeted therapies have added little benefit, with best results in phase II trials reaching a median OS of 19.6 mo and 2 year OS of 37%[3]. Recursive partition analysis had shown that a priori prognostic factors and kind of surgery divide the patients in three classes (III, IV and V) with different prognosis[4], and the benefit of modern therapies concentrates in the better. Present standard therapy showed marginal benefit for class V patients (10.7 mo vs 9.1 mo) in an European Organization for Research and Treatment of Cancer (EORTC)-National Cancer Institute of Canada (NCIC) trial[2].
Several immunotherapy strategies have been attempted and shown to be safe and tolerable. The results of published phase-I/II trials have hinted at efficacy, but they have featured selection criteria and included patient populations, which make comparisons difficult[5-7].
In 2009, we started a phase-II trial for patients with newly-diagnosed GBM based on immunotherapy with ex-vivo tumor lysate-pulsed, autologous dendritic cells (DC) following fluorescence-guided surgery (FGS) using 5-aminolevulinic. After resection, immunotherapy was used as up-front therapy in combination with standard therapy. We hypothesized that the more extensive resection possible with this surgical technique[8,9] would create the best situation to begin immunotherapy, and that immunotherapy itself could be more useful as a front-line strategy. To avoid the potential selection biases shown in other immunotherapy trials[5-7], we aimed at including a wide population of patients and enrolling them right after surgery. Main limitation for entry is that FGS surgery must achieve residual tumor less than 1 cc.
In this report, we present 5 previous cases that constitute a pilot group of this clinical trial.
MATERIAL AND METHODS
Ethics
This pilot study was approved by the institutional review board and the ethical committee of Navarra and all the Spanish regulations concerning human trials were observed.
Patient population
We screened for entry every patient candidate for resection surgery and five consecutive patients with GBM were enrolled in this pilot study, approved by our institutional review board and abiding the norms of the Declaration of Helsinki. We consider most GBM cases candidates for resection surgery, excluding only patients with bilateral extension through the corpus callosum, multiple distant lesions, or ill-defined mass in eloquent areas.
Surgery
FGS was done with a Zeiss© Pentero microscope after Gliolan© administration as previously published[8]. Tumor dissection was carried out along the tumor border defined by fluorescence whenever possible[9]. As much tumor tissue as possible was collected, no ultrasonic aspirator was ever used. FGS allows identifying central viable and invasive portions of the tumor with great predictive positive value, as we have shown previously[10]. After surgery, steroids were quickly tapered and discontinued.
Radiological evaluation
Patients underwent standard magnetic resonance imaging (MRI) in a Siemens Symphony 1.5 T or Trio 3 T unit both preoperatively and 48 h after surgery. Preoperative tumor volume and any gadolinium enhancing remnants were measured using Brainlab planning software after manual segmentation.
Pathological evaluation
All samples were evaluated by the same expert neuropathologist and diagnosed as GBM according to the World Health Organization criteria[11]. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was assessed by polymerase chain reaction.
Vaccine production and administration
All manipulations necessary to produce the vaccines were carried out under good manufacturing practice conditions.
After receiving the tumor sample, a single cell suspension was produced by mechanical disaggregation using the GentleMACS™ Dissociator (Miltenyi Biotec). The cell suspension was immediately frozen and stored until use. To prepare the tumor cells lysate, tumor cells were thawed and subjected to four cycles of freezing and thawing. After centrifugation, the supernatant was filtered with a 40 µm Falcon filter (BD Biosciences) and the amount of proteins obtained was quantified using the BCA™ Protein Assay Kit (Pierce). After irradiation (54 Gy), the tumor lysate was frozen. Central and invasive portions of the tumor were processed separately.
DC were generated from CD14+ monocytes. Peripheral blood mononuclear cells (PBMC) were collected from patients through leukapheresis. CD14+ cells were then selected by immunomagnetic separation using a CliniMACS™ (Miltenyi Biotec) and cultured at 2 × 106 cells/mL in AIM-V (Gibco) supplemented with antibiotics, 1000 UI/ml of interleukin-4 (IL-4) (R and D Systems) and 1000 UI/mL of granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leukine™, Genzyme Corporation,) in culture bags (CellGenix). IL-4 (500 UI/mL) and GM-CSF (500 UI/mL) were further added on the fourth day, and cultured cells were harvested on the seventh day. These immature DC were adjusted at 107 cells/mL and pulsed with autologous tumor lysate during 2 h at 37 °C and 5% CO2. At that time, to induce DC maturation, 50 ng/mL of tumor necrosis factor (TNF)-a (Beromun™, Boehringer Ingelheim), 1000 UI/mL of interferon (IFN)-a (Intron A™, Schering Corporation) and 20 ng/mL of Poly I:C (Amersham) were added to the medium, and cells were placed in culture bags at 2 × 106 cells/mL. Mature DC were harvested on the eighth day and frozen in aliquots until use.
Surface markers of both immature and mature DC were ascertained by flow cytometry using a FACSCalibur™ (Becton-Dickinson), whereas data were analyzed using the Cell Quest Pro software (Becton-Dickinson). For each dose of vaccine, one aliquot of frozen DC was thawed. Ten million cells per vaccination were considered the optimal dose, though fewer cells were actually employed in some instances, as specified in the results section. To address the issue of quality assurance, an aliquot of the final product underwent sterility controls.
Treatment schedule
All patients started radio-chemotherapy following Stupp protocol[2]. The intention was to administer 12 cycles if well tolerated.
The leukapheresis was carried out usually within two weeks from surgery, at least seven days after last dexamethasone dose. First DC administration was scheduled prior to radiotherapy, second one, three weeks after radiotherapy, followed by two monthly, four by-monthly, and later quarterly until the end of all available doses. The actual number of doses received by each patient is specified in the results section. During temozolomide treatment, DC were administered on day 21 of the cycle to benefit from the recovery form leukopenia.
Clinical assessment
Patients were followed clinically each month during the first year and every 2 mo thereafter.
MRI was carried out at 3 mo intervals or within a week from any neurological worsening. A neuroradiologist evaluated the MRI using the Response Assessment in Neurooncology criteria criteria[12]. When progression was observed, any subsequent therapy was left at the discretion of the treating oncologist. All patients were followed until death.
OS of the patients in this pilot study was compared to that of patients undergoing standard therapy with the published nomograms from EORTC 26981/22981 NCIC trial[13] and to a matched historic cohort. The historic cohort was selected from patients operated in our center with FGS, and similar age, Karnofsky performance status (KPS), recursive partitioning analysis (RPA), MGMT methylation status and residual tumor volume (four complete resections, one less than 1cc). From the nomograms, each patient was assigned an expected OS; if our treated population survival had been similar to the EORTC series, the proportion exceeding median OS should have been 0.5. Binomial test with proportion 0.5 was used to assess statistical relevance. The OS of the treated patients was compared also to historic controls using log-rank (Mantel-Cox).
Immune response evaluation
Tumor-specific cellular immune responses were assessed by three independent, controlled methods: T-cell proliferation assay, cytokine release enzyme-linked immunosorbent assay (ELISA) and interferon-? (IFN-?) enzyme-linked immunosorbent spot (ELISPOT) assay as previously published[13]. For the T-cell proliferation assays, PBMC were stimulated with 20.000 DC pulsed and matured. The stimulation index (SI) was calculated as the ratio of the response to tumor lysate or pulsed DC over the mean response in the absence of tumor material. A response was considered positive when the SI was > 2 at least at two different time points. IFN-? and TNF-a production was measured by ELISA (Pharmingen). A response was considered positive when IFN-? and TNF-a production was > 2 than in controls at least at two different time points.
The number of IFN-? producing cells was measured by ELISPOT (Mabtech). PBMC were stimulated with 20.000 DC pulsed with tumor lysate and matured. A response was considered positive when the number of spots was > 2 than in controls at least at two different time points.
RESULTS
Patient characteristics
Five patients were screened and included (Table ).1). Mean age was 66 years, median KPS was 70, four patients were RPA class V and one was class IV. MGMT promoter was unmethylated in one and methylated in four cases. Mean preoperative tumor volume was 54 cc (34-112)
?
Resection was total in three cases, while the other two cases had 0.25 cc and 0.27 cc residual tumor
Feasibility
Enough tumor lysate and DC were available in all cases. From three patients (UPN 1, 4 and 5), we separately received material from both central and invasive portions of the tumor. Both tumor components were used for vaccine production in all three cases. In the remaining two cases, only material from the central portion was obtained. The amount of tumor lysate used to pulse the DC of each patient is specified in Table Table22.
Summary of vaccine production data
For three patients (UPN 1, 2, 5) one leukoapheresis sufficed to produce the amount of DC to be used for several doses (16, 16 and 18, respectively). In one case (UPN 4), two leukoaphereses were instead necessary, since the number of DC obtained allowed the preparation of 4 and 11 vaccine doses, respectively. The fifth patient (UPN 3) underwent only one leukoapheresis, though the production of DC was limited to 4 doses, because at the time of his first DC vaccination radiological signs of a possible progression had already been detected.
The cells used for vaccination are mature DC. They strongly express CD33 as well as CD11c and CD209. Vice versa, they lack CD19, CD3 and CD14 expression and have high expression of HLA-DR, CD40, CD86 and CD83 (data not shown).
UPN 2 received only four vaccine doses because of rapid clinical deterioration, while UPN 3 received only four doses due to the low cell amount obtained through the leukoapheresis. The other patients (UPN 1, 4 and 5) received 11, 15 and 12 vaccine doses, respectively.
UPN 2, 3 and 4 experienced administrative delays and could not receive the first dose prior to radiotherapy. As for UPN 2 and 3, possible early radiological progression signs were detected at the time of the first vaccination. UPN 1, 4 (except for the timing of the first vaccine dose) and 5 followed the vaccination calendar as described above without deviations.
Immune response
Results are shown in Table Table3
.3. PBMC proliferation after stimulation with tumor lysate-pulsed DC was detected in all three patients (UPN 1, 2, 5) in whom the test was performed (Figure (Figure1).1). In the three cases, autologous PBMC stimulated with tumor lysate-pulsed DC also produced not negligible amounts of IFN-? (not shown) compared to controls, and UPN 5 did so even when his PBMC were stimulated with tumor lysate alone from both central and invasive portions (not shown). Vice versa, all ELISPOT tests were negative (not shown).
Safety and tolerability
Neurological deficits after surgery were as follows: one patient (UPN 3) experienced a transient worsening of a right hemiparesis present before surgery; at 6 mo, she still had a 4+/5 right hemiparesis. UPN 2 had a generalized seizure one month after surgery. Toxicity caused by radio-chemotherapy was in line with normally associated with the corresponding regimens.
Neither adverse events nor toxicity attributable to the immunotherapy were observed.
Progression-free and overall survival
All patients have progressed, with a median progression-free survival (PFS) from surgery of 16.1 mo (range: 3.1-20.3). Only one patient was re-operated at recurrence. UPN 2 and 3 had already early radiological progression signs at the time of the first vaccination. In both patients, bevacizumab was started AFTER A SECOND MRI indicated that these signs were not suggestive of pseudo-progression. UPN 2 had a partial response before further progression and death. UPN 3 had a total response to bevacizumab.
Median and mean OS were 27.4 mo and 25.1 mo, respectively (Table (Table1).1). Four of five patients were alive at two years. The number of circulating leukocytes and lymphocytes at the time of each and every vaccination did not correlate with immune response to vaccination and OS. Three patients have died with OS of 9 mo, 27 mo and 27.4 mo, while the other two are still alive at 29 mo and 33 mo. Both living patients are ambulatory and independent. UPN 5 is still receiving treatment with bevacizumab, with total response, while UPN 3 has not received any treatment over the last 9 mo. Contrast enhancement has reappeared around the surgical bed and has been followed for three mo without any symptom.
All five patients exceeded the OS expected with standard of care calculated with EORTC nomograms[13], with a mean difference of 11.4 mo (25.1-13.7). Median OS expected in a group with these prognostic factors would be 12.3. Yet, the OS of our group exceeded it by 14.7 mo (27 to 12.3). Even with only five patients, the binomial test, was almost significant (P = 0.06). The five patients have also lived longed than the historic controls, median 31.2 vs 11.5, this difference was significant by log-rank (Mantel-Cox), P = 0.02.
DISCUSSION
This work presents the results of a pilot group of five patients with GBM treated with experimental immunotherapy consisting of autologous DC pulsed with autologous tumor lysate added to standard therapy.
Several groups have attempted a conceptually similar immunotherapeutic approach in patients with GBM[14]. The strategy appears to be feasible, safe, well tolerated and, at least in some instances, potentially beneficial in terms of PFS and OS. On the other hand, there is not yet a clear consensus on the best DC-based vaccine formulation, dose, route of administration and schedule to stimulate the most effective immune response in the largest possible proportion of patients. Some groups prefer to use immature DC[7,15-23], while we and others focus our efforts on mature DC[24-29] .
In our study, the number of DC used for vaccination differs among patients, but we think that, within certain limits, this does not condition the effectiveness of treatment. We simply used the number of DC available in each and every case.
Given our extended experience with idiotype vaccines against B-cell malignancies[30], we are trying to build a solid foundation for our GBM active immunotherapy keeping into account similarities and differences between the two customized strategies. The former deals with an indolent disease, targets a known tumor-specific antigen, has shown biological and clinical efficacy as well as clinical benefit, but has not passed the test of randomized clinical trials[31]. The latter deals with a dreadful disease, targets unknown tumor-associated and/or-specific antigens, has formally shown biological efficacy-e.g., immune responses induced by vaccination, but not yet clinical efficacy and clinical benefit[13]; moreover, it has not yet completed a randomized clinical trial. The fact that clinical efficacy (e.g., the ability to kill tumor cells in vivo) cannot be easily shown in GBM, given the lack of a suitable surrogate marker, is not a major concern as long as we can show clinical benefit, that is improved OS and/or PFS.
Some very long survival times have been reported. However, efficacy is not yet proved. An important issue in previous immunotherapy trials for GBM is the inclusion criteria, as most require the patients to be off steroids after surgery and after radiotherapy[5-7,22], or exclude patients who had radiographic progression after standard radio-chemotherapy[32]. The selection creates important biases in any efficacy comparison, as the patients with very early progression clearly represent the worst cases[33]. We aim at treating a wide base of patients with different ages and functional status, while we also enroll the patients from surgery precisely to avoid these biases.
The only limitation of our selection criteria is that we enroll only resectable cases. The amount of residual tumor is also accepted as very important for the survival and for the efficacy of immunotherapy. This study includes fluorescence guided resection and the intention to make a gross total resection as part of the treatment protocol. So, ours is not a group of patients selected a posteriori because they underwent a good resection, but a treatment scheme designed to achieve benefit from the combination of maximal surgery, radiochemotherapy, and immunotherapy. Figure
Figure22 shows representative MRI slides of the five cases to clarify this important point. We have previously shown that with experience in FGS, the inclusion criteria of less than 1cc can be reached in a majority of patients including complex surgical cases[9]. Others have showed similar results with intraoperative MRI[34].
The other difference in our treatment schedule from previous works using immunotherapy added to standard radio-chemotherapy consists in beginning vaccination prior to radio-chemotherapy. We have shown that in the typical 4 wk interval between surgery and radio-chemotherapy there is time to manufacture the vaccines and administer the first dose. We think that this dose can help to promote a faster increase of the response from subsequent doses, even though we do not expect an immediate benefit during the period of immunosuppression induced by radiochemotherapy.
The patient sample presented here is not selected by young age, good functional status or absence of early progression. Therefore, it is representative of a wide population of GBM patients; 80% were in RPA class V and mean age was 67 Patients with first-line immunotherapy in the work of Prins et al[5] had a mean age of 49.7 years and 60% were RPA class III, while in the work of Ardon et al[6] mean age was 50.3 and 7 out of 8 patients were RPA IV, and one RPA III.?
Despite the small number of cases, the survival time is clearly unexpected for a group with these characteristics. MGMT promoter methylation was the only positive prognostic factor, and yet the cohort with methylated MGMT promoter in the EORTC-NCIC shows a median OS of 23 mo[2], while all of our 4 methylated patients have lived longer than 27 mo, with two still alive. The median OS in our group exceeds the OS expected using the EORTC nomograms[13] by almost 15 mo (27.0 to 12.3). Even with the intrinsic limitations of the small sample size, we conclude that this DC-based immunotherapy is likely to have added to the results of standard of care and provided an OS clearly superior to the expectations, suggesting a strong benefit from immunotherapy in an unfavorable group of patients.?
ACKNOWLEDGEMENT
This work is dedicated to the memory of Dr Javier Pérez Calvo, who over the years was an instrumental driving force of the overall program and who sadly died in August 2012 after fighting against leukemia since January 2011.
COMMENTS
Background
Glioblastoma multiforme is the most frequent brain tumor and is all but incurable. Even with the most sophisticated surgical approaches, including fluorescence-guided complete or near complete resection, followed by standard of care the typical survival does not go beyond 12-15 mo.
Research frontiers
Tumor lysate-pulsed dendritic cell vaccination is an experimental type of customized, active immunotherapy currently under development. It aims at educating the patient’s immune system in order to prevent tumor reoccurrence/progression. As such, it is meant to be administered shortly after the maximum response to previous therapies.
Innovations and breakthroughs
In this pilot study, the authors enrolled five consecutive glioblastoma patients with poor prognosis. In most cases, they would have not been enrolled in the previous clinical trials mentioned above. Yet, following fluorescence-guided surgery and tumor lysate-pulsed dendritic cell vaccination, they all experienced remarkable progression-free survivals. In a couple of cases, this result is still ongoing over two years after surgery.
Applications
The study results suggest that tumor lysate-pulsed dendritic cell vaccination, after fluorescence-guided complete or near complete surgery, should be attempted in all resectable patients with glioblastoma multiforme, not only in those with better prognosis.
Terminology
Fluorescence - guided surgery: it is a surgical technique enhancing the ability of the neurosurgeon to remove nearly all the tumor by a better visualization of the tumor resection margins; tumor lysate: it is the product of mechanical disaggregation of the tumor removed during surgery; Dendritic cells: autologous - therefore patient - specific - antigen presenting cells which are derived from monocytes and matured in vitro.
Peer review
Despite the small number of patients enrolled in this pilot study, the results of this treatment are extremely promising and warrant expansion in the currently ongoing, larger clinical trial.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536842/
Whole tumor lysate is the entire mer that can be broken down into small proteins peptides that can then be pulses with dendritic cells for antigen presentation.
Self-Ag are the antigens in question. For instance, a common one is HER2. This is an antigen that is over expressed in many cancers but it is not found in normal tissue. The idea is to target the HER2 antigen. But the issue is not all HER2 epitomes are equal. Having the full TUMOR lysate of the HER2 23 Mer Protein then allows the cancer protein to be broken down into the smaller appropriate MHC class presentation epitomes.
"The Role of Antigen Processing in tumor cells to present targets for killing: As described above, it is now possible both in the lab, and on a computer, to identify or predict which small peptide fragments will bind to individual MHC Class I or Class II molecules. However, being able to generate immune responses to isolated peptide is only half of the story, as tumor cells must actually display these same peptides on their cell surface, bound to the same MHC molecules for a killer T cell to actually kill. Some synthetic peptide vaccines can induce apparently strong killer T cell responses by‘fitting’ into Class I MHC molecules, but are still poor vaccines due to the absence of the matched natural target displayed on tumor cells. To understand this paradox we must understand antigen processing. Inside of all cells, tumor cells included, are small barrel shaped organelles called proteasomes who’s function it is to ‘process’ proteins, like HER-2/neu, into the small target sized peptide fragments. The specific fragments that they generate by a proteasome (or immunoproteasome) are a function of the protein clipping enzymes or proteases that are inside of these barrel shaped organelles, creating a predictable set of peptide fragments from any given protein."
This Immune Epitope Database and Analysis Resource:
http://www.iedb.org
Answers: 2; 1; 2; unknown.
I'm going mostly silent while we wait. Just shared a few interesting abstracts. :)
Long term survival is not as easy as some perceive to come by. Immunotherapy has the most. Here are a couple of abstracts that I think you'll find interesting. One is a retrospective review of the patients that can be found from 2000 - 2010 period. The other is that can be found with ICT-107 clinical trial. Last we heard there are 10 survivors in the Compassionate Use Arm (55 patients), each without an official Progression Free Survival event. That's 26 patients (Indeterminates + 1 pseudo)/10 survivors = 38% long term survival rate for possible psPd group; or 55 CUA/10 Survivors = 18% Long term Survival rate of the entire CUA. Very much looking forward to seeing what OS looks like in the DCVax-L main arm. :)
PDCT-14. CHEMOTHERAPY BENEFITS SOME BUT NOT ALL HIGH GRADE GLIOMA PATIENTS
Yang Liu Christine Pittman
Neuro Oncol (2016) 18 (suppl_6): vi149. DOI: https://doi.org/10.1093/neuonc/now212.618
Published: 07 November 2016
Abstract
BACKGROUND:
Malignant glioma is frequently fatal. The current standard of care prolonged survival in phase III clinical trials. It is unclear though if these survival gains extend to the entire population of glioma patients.
METHODS:
We retrospectively collected patients registered in a population-based database for primary high grade gliomas (HGGs, n = 363) treated in Rochester, NY from 2000 to 2014. We analyzed survival trends and evaluated treatment efficacies for these patients. To externally validate our local population, we also performed survival and medication analysis for glioblastoma (GBM) patients from The Cancer Genome Atlas (TCGA) database.
RESULTS:
The median age at diagnosis was 61 years. The majority of patients were white (94.5%) with GBM (77.7%). Most (84.3%) had died (all causes) during the follow-up interval. Overall, patients who received combination treatment of surgery, RT and chemotherapy have better survival (median 490.0 days) than those who received combination of surgery and RT (median 239.0 days, p<0.001) or surgery alone (median 95.0 days, p<0.001). We further grouped patients into three time periods for comparison: 2000 to 2004, 2005 to 2009, and 2010 to 2014. We found no appreciable differences in the median, 6-month, and 2-year survivals between each time interval (median survival time: 368.0 vs. 360.0 vs. 358.0 days, respectively) for all HGGs. Survival of GBM patients slightly increased, but this was exactly offset by worsening survival rates for grade III patients. While survival did not measurably change, our temozolomide administration increased significantly over the time (42.1% vs. 80.5% vs. 73.1%). Bevacizumab usage rose from 6.3% to 50.3% as well during the time. Similar flat survival trends in the face of increasing chemotherapy use were seen from the TCGA cohort. Our data indicate that chemotherapy, while effective, has benefits to a smaller group of patients than currently receive it.
They only looked at data for patients who completed 6 or 6 or more Adjuvant TMZ cycles; and from there they analyzed both PFS and OS to determine the effects of whether long term adjuvant TMZ makes sense. The conclusion was that extending TMZ beyond the 6 adjuvant cycles does not extend OS in all patients, and so patient management, I imagine will be to keep standard of care at 6 adjuvant TMZ cycles, and only do 6 or more cycles of TMZ in patients who appear to be responding to TMZ IMO.
ATIM-14. FIRST KOREAN EXPERIENCE OF DENDRITE CELL-BASED IMMUNOTHERAPY IN PATIENTS WITH PRIMARY GLIOBLASTOMA
Jaejoon Lim Kyung gi Cho
Neuro Oncol (2016) 18 (suppl_6): vi20-vi21. DOI: https://doi.org/10.1093/neuonc/now212.079
Published: 07 November 2016
Abstract
OBJECTIVE:
Dendritic cells are antigen presenting cells that recognize antigens and trigger an immune response in human immune system. Dendrite cell-based immunotherapy (DCI) has the potential to target and eliminate GBM cells. We evaluated the safety and efficacy of DCI in patients with primary glioblastoma.
MATERIALS AND METHODS:
The dendritic cells sensitized with self-tumor lysate, WT1 and KLH are intradermal injected on upper arm. We administrated the dendritic cells four times every two weeks and twice at intervals of two weeks after the 4weeks of rest period. We followed up patients two years. Treatment response was evaluated with CT and MRI, and immune response was evaluated with T cell proliferation assay and ELISPOT test. The Control group was set up to histological reference (newly diagnosed, standard treatment completed 24 patients).
RESULTS:
Thirteen patients received this immunotherapy. The total 83 related adverse events occurred. The eighty-two (Grade I) and one (Grade II) reactions were not serious adverse effects. Immune response (antigen specific IFN-? and T-cell proliferation) was confirmed. The median progression free survival (PFS) was 15.6 months and the median overall survival (OS) was 28.4 months. DCI led to an extension of PFS (8.2 months; wilcoxon p = 0.084) and OS (16.1 months; wilcoxon p = 0.029) compared to control group. In IDH-1 non-mutation with gross total resection patients group, DCI showed 27 months of survival advantage (wilcoxon p = 0.019) compared to control group.
CONCLUSION:
Dendritic cell-based Immunotherapy in patients with primary glioblastoma is comparative safe and had minor adverse reactions. DCI results in a longer PFS and OS compared to histological reference and well-tolerated. DCI is a good complementary treatment for primary glioblastoma.
She was specifically reference the exclusion criteria scan in her comments, the Post RT MRI. Patients who should have not been EXCLUDED were excluded because they could not confirm or deny whether or not the patients had early progression or Pseudoprogression. She was not concerned if pseudoprogression patients made it into the study, her comments were about them being excluded.
Linda Liau's comments around minute 34:
"So there is a couple things...We designed this trial about seven years, almost eight ago now, so there is a couple of things that I think we have learned from this trial that MAY AFFECT THE FINAL RESULTS and I think it has helped us to kind of learn more about how to design future trials, in the future. One ISSUE was that at this POST RADIATION MRI SCAN, if the patients had progressive tumor they were actually EXCLUDED from the trial. They were put into the separate informational arm. And the thought about that was that, about that, our prior experience was that the phase I trials, if we had a big bulky disease or not even bulky disease, PROGRESSIVE disease, those patients did not respond as well because if your tumor is growing exponentially you don't have enough time to mount an immune response to the tumor and those patients at least what we saw did not benefit. So that was the rationale for excluding that... early progressors in that trial. Unfortunately what we learned over the years is that determination of the early progression is difficult because of the issue of pseudo progression so there may be some patients that were EXCLUDED that probably SHOULD NOT HAVE BEEN EXCLUDED or vice versa." -- LLiau
Yes, it actually speaks to early Pseudoprogression management. But yet, AVII thinks that the Pseudoprogression scans that showed up within the first 12 weeks after chemoradiation in this Phase III that the blinded Radiologist decided the response scan should result in a crossover change in therapy. I doubt any blinded Radiologist will be able to distinguish that the pseudoprogression from TMZ than Pseudoprogression that may be vaccine related. And as I continue to state, standard the care as it relates to possible Pseudoprogression scans following Concomitant RT/ TMZ therapy has been standardized. Any Pseudoprogression scan that showed up on Month 2 scan, I have no doubt that the patient (s) continued on their adjuvant TMZ and Vaccine (placebo or treatment) and follow up scans determined if/when the patient was a true early progression patient.
https://www.slideshare.net/mobile/cancerassassin1/neurooncology-for-the-radiation-oncologist-gliomas
Thanks eagle. The 248 primary endpoint was expected to have been reached in November 2016 timeframe (from their NCT registry). Sadly most of these progression patients will pass, but not all in the same month either. And then there a likelihood that additional progression events have been accumulating and will continue. It's been 3+ months since November. Not all the 248+ patients PFS events occurred that month, perhaps, for example, only 10 of the 248 patient events occurred in November, and 10 of 238 patients events occurred in October (4+ months out); and 10 of the 228 events occurred the month before (5+ months out) and so on, and so on. Progression to death can typically be 4-7 month window for non-responders and typically 9-11 months for salvage responders. Very few progression patients survive beyond 18 months. And that means it's only a short matter of time before majority of these 248+ PFS events convert to 233 OS events, sadly.
I'm really sorry for your loss highwayman. Hopefully the disease memories you have of him will fade to the background and the amazing ones will be what you recall most. My sincere condolences.
By the end of this Q1, which is a few weeks away, I will have a total of 267 enrolled patients out 27+ months from surgery. This trial is waiting on 233 overall survival events.
Remember randomization is about 3 months after newly diagnosed surgery. And so tag on 3 months to the numbers below to find the nGBM true survival outstanding information. For instance in Q1 2014 (ran Jan 1 - March 31, 2014) those 187 patients are all 36+ months from their randomization date and 3 months more for surgery. But only 6-8 or so would have been enrolled in March 2014 which is 39 months out from screening surgery. The rest (or 180-182 patients) would be at least 40 or more months out from their newly diagnosed GBM. Given enrollment ran for years the 267 patients that are going to be out 27+ months out from surgery. Another 60 or so will be out 21 months minimum from surgery. And yet, OS has not been reached to our knowledge (yet).
By Quarter ending date/year: Enrollment cumulative #)//cumulative randomization (placebo:vaccine)
Q3 2008: 11 patients (3:8)
Q3 2011: 15 patients (5:10)
Q4 2011: 23 patients (8:15)
Q1 2012: 35 patients (12:23)
Q2 2012: 49 patients (16:33)
Q3 2012: 63 patient (21/42)
Q4 2012: 83 patients (28/55)
Q1 2013: 103 patients (34/69)
Q2 2013: 125 patients (41:84)
Q3 2013: 147 patients (49:98)
Q4 2013: 169 patients (56:113)
-- 66 patient IA event, old SAP
Q1 2014: 187 patients (62:125)
Q2 2014: 205 patients (68:137)
Q3 2014: 223 Patients (74:149)
Q4 2014: 245 patients (81:164)
Q1 2015: 267 patients (89:178)
Q2 2015: 295 patient (99:196)
Q3 2015: 331 patients (111:220)
Surgery is always before enrollment. And surgery is expected to be around 3 months earlier. So for instance in a couple of weeks 245 patients will be out at least 30 months from their newly diagnosed surgery. Most of the Psuedoprogressions will have been removed by the exclusion criteria prior to enrollment. The best responders are Pseudoprogression. I do not know of any placebo that has about 100 extra patients and goes out 30 months from surgery and still hasn't reached 70% of enrollment events. In fact, what the company suggested is that we have to wait a few more months. In a few more months (June 30) at least 245 patients to be out 33 months from their nGBM diagnosis; with another 86 patients ranging from 22-32 months out from surgery according to my estimates (only a handful at 22 months). If we are still without a 233 OS event crossing in a few months (from 331 patient enrollment) I can not see how any one can claim the blinded and waiting results are a placebo. Not a sole can model 331 patients being out over 2 years soon. Well some are reluctant to let go of their confirmation bias. Oh how some cling to holding to survival skepticism at all cost. Survival does not lie.
So there's that. :)
Sure, I had altered slightly as I originally had enrollment stopping with August 2015 screening halt.
US planned enrollment 216 patients
UK planned enrollment 24 patients
Germany planned enrollment 87 patients
Canada planned enrolled 21 patients
Q3 2008: 11 patients
Q3 2011: 4 patients (15)
Q4 2011: 8 patients (23)
Q1 2012: 12 patients (35)
Q2 2012: 14 patients (49)
Q3 2012: 14 patient (63)
Q4 2012: 20 patients (83)
Q1 2013: 20 patients (103)
Q2 2013: 22 patients (125)
Q3 2013: 22 patients + UK screens (147)
Q4 2013: 22 patients (169)
-- 66 patient IA event, old SAP
Q1 2014: 18 patients (187)
Q2 2014: 18 patients (205)
-- Expanded access arm added on ClinicalRegister, pseudo arm likely closed.
-- Fraunhofer IZI site clears, German joins trial;
Q3 2014: 18 Patients + Germany slow (223)
Q4 2014: 22 patients (245)
Q1 2015: 22 patients + Canada screens (267)
Q2 2015: 28 patients (295)
Q3 2015: 36 patients (331)
348 patient planning assumption -- ended with 331 patients (17 likely fell short in Canada (or Germany); US + UK finished in late 2014 (UK)/early 2015 (US).
Quarter Year: Enrollment (cumulative #)//Enrollment Assignments per quarter placebo:vaccine //Randomization cumulative = cumulative enrollment (placebo:vaccine)
Q3 2008: 11 patients //3:8 (3:8)
Q3 2011: 4 patients (15) //2:2 (5:10)
Q4 2011: 8 patients (23) //3:5 (8:15)
Q1 2012: 12 patients (35) 4:8 (12:23)
Q2 2012: 14 patients (49) 4:10 (16:33)
Q3 2012: 14 patient (63) 5:9 (21/42)
Q4 2012: 20 patients (83) 7:13 (28/55)
Q1 2013: 20 patients (103) 6:14 (34/69)
Q2 2013: 22 patients (125) 7:15 (41:84)
Q3 2013: 22 patients + UK screens (147) 8:14 (49:98)
Q4 2013: 22 patients (169) 7:15 (56:113)
-- 66 patient IA event, old SAP
Q1 2014: 18 patients (187) 6:12 (62:125)
Q2 2014: 18 patients (205) 6:12 (68:137)
-- Expanded access arm added on ClinicalRegister, pseudo arm likely closed.
-- Fraunhofer IZI site clears, German enters;
Q3 2014: 18 Patients + Germany slow (223) 6/12 (74:149)
Q4 2014: 22 patients (245) 7:15 (81:164)
Q1 2015: 22 patients + Canada screens (267) 8:14 (89:178)
Q2 2015: 28 patients (295) 10:18 (99:196)
Q3 2015: 36 patients (331) 12:24 (111:220)
Or said another way:
By Quarter ending date/year: Enrollment cumulative #)//cumulative randomization (placebo:vaccine)
Q3 2008: 11 patients (3:8)
Q3 2011: 15 patients (5:10)
Q4 2011: 23 patients (8:15)
Q1 2012: 35 patients (12:23)
Q2 2012: 49 patients (16:33)
Q3 2012: 63 patient (21/42)
Q4 2012: 83 patients (28/55)
Q1 2013: 103 patients (34/69)
Q2 2013: 125 patients (41:84)
Q3 2013: 147 patients (49:98)
Q4 2013: 169 patients (56:113)
-- 66 patient IA event, old SAP
Q1 2014: 187 patients (62:125)
Q2 2014: 205 patients (68:137)
Q3 2014: 223 Patients (74:149)
Q4 2014: 245 patients (81:164)
Q1 2015: 267 patients (89:178)
Q2 2015: 295 patient (99:196)
Q3 2015: 331 patients (111:220)
My understanding is that an interim was expected to hit sometime between Q2 and Q3 of 2015. I'm honestly not sure if it was 60% of 248 primary endpoint events or the 80% of 248 primary endpoint events. There was a new Statistical Analysis Plan in place as of August 2014. None of us have seen that SAP. Given enrollment was meant to be 348 patients, my guess is that the first IA may have been the 60% of events. None of us are sure if they did that IA. However, given we already knew the company would continue the trial to the end, per the 2014 year end shareholder meeting, I believe they avoided the hoopla over it as the trial was under a screening halt. It would have been inappropriate in my opinion to make a fuss about it as it could have been construed overly positive.
Whatever Interim did pass (either 60 or 80% of 248 events), we do know that it's crossing was expected by Q3 2015. Flip will likely know which one they were expecting. I did not hear the reference to the Interim. But, by the August 2015 halt we do know that 306 patients were enrolled at that point (randomized 2:1). In my view the progression and survival events for that interim (148 (60%) or 198 (80%) events) depends on enrollment. Events that came from the vaccine would likely be mostly be coming from patients who were enrolled at least a year earlier (Q2 2014 or earlier). By then 137 vaccine patients enrolled at that point per my estimates. Events from the placebo could come from standard of care patients that were no earlier than Q1 2015. By that point 89 placebo patients were enrolled according to my estimates.
Listen AVII. I'm sick of you misrepresenting my argument about confirmation scans. What you blast about shareholders is pure garbage and nonsense. Where did I ever write Jefegbm's 9 PFS Month scan required confirmation!? I NEVER wrote anywhere that progression at 9 months needs confirmation. They obviously have many scans at that point. They have a history of his progress. I only said the VERY first scan after initiating vaccine, the Month 2 scan, the scan initiated within the first 12 weeks after concurrent chemoradiation needs confirmation. It is the Month 2 scan that is retrospectively reviewed. You add context to my words to mean all scans. I correct you 101 times at minimum, and you still continue to do it. You purposely are skewing my debate to misrepresent me. How many corrections do you need? Consider this 102.
It is bizarre how AVII can go from discussing measurable disease to non-measurable disease and interchange them as if they are somehow the same. They are not the same. I don't think he gets that they are not the same.
The mystery FLAIR is likely speaking of NON-MEASURABLE disease on T2/FLAIR. These can show-up inside the field of radiation. They can also occur occur outside the field of radiation (T cells showing up to combat a new small TUMOR that is not present yet on image scans). TUMORs that are really small are not often picked up early on MRIs. These new tumors may signify disease failure. The point of T2/FLAIR is to catch non-measurable disease progression before it becomes measurable and certain treatments mask (anti-VEGF) what is going behind the BBB scenes by causing false-positive T1 enhancement responses. Avastin for instance can make it appear as therapy is working by removing presence of enhancements of residual disease, and that is why RANO incorporates non-enhanced TUMOR. If FLAIR shows up, and residual tumor does not meet size "out" rule, it automatically fall into a MONITOR state. It doesn't matter when it shows up. If mass does not equal progression event "size", when added to preexisting TUMOR, then it falls into the monitor with follow-up scan(s) category until it gets better or worse. And so, T cells infiltration from an effective immunotherapy can sometimes be seen on T2/FLAIR scans. We all want the scans to get better, and for the T cells to do their job. Whether they do or not, and whether the totality of all pre-existing lesions grew > 25% from treatment BASELINE (Month 2) will determine if the patient fails or responds to treatment therapy.
From the protocol it states this about non-enhanced lesion:
• "Unequivocal progression of non-measurable disease (either non-enhancing disease seen only on T2/FLAIR images or enhancing disease not meeting size criteria for measurability), such that there is confidence that tumor growth has occurred;44 Radbruch et al. 2010: Neuro Oncol. 2011 Dec 6."--Phase III protocol RANO
"4.2. Non-enhancing Lesions
In addition to enhancing lesions, non-enhancing lesions on T2/FLAIR images are reviewed when evaluating GBM response. Non-enhancing lesions are not measured but instead are monitored for changes in size. It is important to note that the extent of the non-enhancing component of the tumor can be difficult to determine since localized swelling and damage caused by radiation have a similar radiographic appearance. Changes in T2/FLAIR signal that suggest presence of an infiltrating tumor include mass effect, infiltration of the cortical ribbon, and location outside of the radiation field. " -- RANO criteria
No, that is not what we were arguing about. Instead we were mostly arguing whether any patients who exhibit Apparent Early Tumor Progression (AETP) on Month 2 scan would (you) or would not be (me) removed as a progression free survival event. (Brad's scan is another subject entirely; you saw a measurable BASELINE scan that grew 2 weeks after initiating therapy; and I saw a non-measurable baseline scan that required retrospective monitoring of possible 2 weeks post treatment enhancement induced scan changes.)
As for this Phase III Month 2 scan, you felt that MacDonald considered AETP patients (>25% of enhancing disease) that showed up after chemoradiation as an automatic PFS event. Whereas, I perceive that MacDonald is now RANO and retrospectively reviews all the POST BASELINE scan (Month 2 in this Phase III) by use of follow-up scan to separate true TUMOR progression from Pseudoprogression.
The first three months after concurrent chemoradiation are known to include Pseudoprogression events that mimic progression. That phenomenon showing up in the main arm after concurrent RT/TMZ may have been reduced due to the exclusion criteria (removal of evidence of disease patients). However, I doubt Pseudoprogression RT/TMZ induced early scans of new "mimic progression" appearances will have completely gone away. Given the fact that the trial was randomized by MGMT status, I see both arms as having been at equal percentage risk of early scans after concurrent RT/TMZ mimicking that phenomenon. But it doesn't matter as I still see that a follow-up period is necessary and it is done in standard practice to confirm true progression.
As you are well aware the RANO criteria, which became standard as of 2010, does not call disease progression mimicking patients official "progression" during the first 12 weeks after chemoradiation therapy as it needs to account for Pseudoprogression first. You think that somehow this trial will not be abiding that RANO rule. You think this trial will have no choice but to blindly call all Apparent Early Tumor Progression (AETP) --that may end up being psPD -- as progression free survival event. You perceive that as MacDonald. Whereas, I think early scans are retrospectively reviewed in order to confirm a progression threshold has been crossed, and that is a standard practice now, regardless of criteria. Pseudoprogression is known to occur in the standard of care patients during the first 12 weeks after chemoradiotherapy and I see concurrent RT/TMZ being a possible culprit of AETP scans, I think it is IMPOSSIBLE to call scans within the field of radiation "progression" without a retrospective review.
I also think because that in clinically practice that RANO rule for looking out for RT/TMZ responding patients (in order to avoid prematurely stopping or altering effective therapy) and that Psuedoprogression rule can not be bypassed. Since STUPP protocol became standard it quickly became apparent that true early TMZ failure can only be determined with serial scans. There is no imaging biomarker that "automatically" confirms GBM progression for newly diagnosed concurrent RT/TMZ patients. And since TMZ was brought upfront with radiation the incidence of Pseudoprogression was addressed by that RANO clause. Patients who have not progressed can be determined by follow-up. As such I feel that no IRB will approve a "automatic" fail image biomarker be used in this Phase III trial, particularly as one does not exist an image biomarker for GBM progression.
I also believe that the IRB will not allow any AETP scan to be automatically determined as treatment failure in that < 12 week post concurrent RT/TMZ period. Adjuvant TMZ was also being given in that immediate Post RT period. It will be impossible to know if main arm patients Month 2 scans are TMZ treatment related Pseudoprogression effects. And considering that TMZ follow-up imaging is standard now to look out for early Psuedoprogression, I see it as impossible to rule any scan automatic progression in that <12 week window. I see this approach being used on Month 2 scans:
Response Assessment
Central review of pre- and postcontrast T1-weighted and FLAIR images was performed by an independent radiologist who was blinded to clinical data and who obtained standard bidimen- sional measurements on T1-weighted postcontrast images. The reader was also blinded to the order of the imaging time points to avoid bias in tumor measurements from expected treatment effects. Clinical evaluations were performed by the treating oncologists. Tumor response was determined according to the updated Response Assessment in Neuro-Oncology (RANO) criteria for malignant gliomas [2], taking into account clinical performance, dose of steroids, dimensions of contrast- enhancing lesions, and extension of tumor-related FLAIR signal abnormalities. Patients who demonstrated signs of progression on imaging inside the radiation field during the first 12 weeks after completion of radiation were considered to have apparent early tumor progression (AETP) and (if clinically feasible) were maintained on the same treatment regimen and imaging surveillance. During follow-up, patients with lesions that maintained growth despite treatment were considered to have TTP. PsP was diagnosed in patients with stable or regressing lesions for a period of at least 6 months without changes in therapy (Fig. 1). Repeat biopsies or resections at the time of AETP were not deemed necessary by the treating neuro-oncologists for pathologic analysis in most cases, given the increasing recognition of PsP [5, 21–23].
Gord Downie:
http://www.cbcmusic.ca/posts/12553/it-s-unbelievable-gord-downie-s-oncologist
News conference about the musician's GBM diagnosis.