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Tadasana,
Recent article on initiation of radiotherapy:
-Short delay in initiation of radiotherapy for patients with glioblastoma-effect of concurrent chemotherapy: a secondary analysis from the NRG Oncology/Radiation Therapy Oncology Group
Neuro-Oncology, Volume 20, Issue 7, 18 June 2018, Pages 966–974, https://doi.org/10.1093/neuonc/noy017
Conclusion:
Delaying the initiation of concurrent TMZ and radiation for the treatment of newly diagnosed GBM is not detrimental within the accepted guidelines of the 5–6 weeks postoperative period.
Quote:
“Tumors with methylation of the promoter region of MGMT (methylated MGMT) are known to have the greatest magnitude of benefit from the combined chemoradiation treatment, with an impressive 2-year survival rate of 50% for this molecularly sensitive group.”
https://academic.oup.com/neuro-oncology/article/20/7/966/4861801#117988259
There is another error on one of the confidence intervals, that they have not corrected yet.
MGMT un-methylated 162
Survival at 2 years 32.1% (24.5, 9.9)
Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma
Journal of Translational Medicine201816:179
https://doi.org/10.1186/s12967-018-1552-1
© The Author(s) 2018
• Received: 8 June 2018
• Accepted: 19 June 2018
• Published: 29 June 2018
The original article was published in Journal of Translational Medicine 2018 16:142
Correction to: J Transl Med (2018) 16:142 https://doi.org/10.1186/s12967-018-1507-6
Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.
Incorrect author name upon publication:
• Tobias Walpert
The correct author name:
• Tobias Walbert
The affected sentence in the Methods section upon publication, with the error marked in bold:
• In general, approximately 2 g of tumor tissue was needed to produce the full ten doses for the 36-month treatment and follow-up schedule. The vaccine was aliquoted in individual doses and cryopreserved at?<?150 °C [22].
The corrected sentence, with the corrected temperature marked in bold:
• In general, approximately 2 g of tumor tissue was needed to produce the full ten doses for the 36-month treatment and follow-up schedule. The vaccine was aliquoted in individual doses and cryopreserved at?<?-?150 °C [22].
The reference which is cited in the above sentence can be reviewed in the original article.
Some lessons we can take from the study below:
Quote:
“The results of the INTELLANCE 2 trial presented in November showed that those treated with Deputax-M in combination with temozolomide (TMZ) possibly did slightly better than those treated with just TMZ alone. However, these results were not significant enough.
The most recent results, presented at ASCO, include an additional few months of data and indicate that the difference in survival between the Depatux-M and TMZ combination versus TMZ alone is greater than originally shown."
Quote:
“However, because the INTELLANCE 2 trial had already been 'unblinded', meaning that the researchers and participants found out who took which treatment, the company cannot use these results to file for regulatory approval. “
Quote:
"These developments demonstrate the challenges faced by companies, as they have to balance the risk of reporting trial results too soon against the curiosity of understanding whether a treatment works."
https://www.thebraintumourcharity.org/media-centre/news/research-news/positive-results-recurrent-glioblastoma-drug/
Positive results from a drug treating recurrent glioblastoma.
Thursday 28 June 2018
New data presented at the recent American Association of Clinical Oncology (ASCO) meeting in Chicago by Abbvie, a pharmaceutical company, provides hope for those diagnosed with a glioblastoma
In November 2017, Abbvie presented results of their phase 3 clinical trial, called INTELLANCE 2, at the annual Society of Neuro-oncology meeting. This trial tested a drug called ABT-414 or Depatux-M on individuals with relapsed glioblastoma.
The drug is composed of a combination of an antibody—a type of a protein produced by the immune system—to target EGFR, a type of tumour marker, and a substance that when released inside tumour cells causes them to die.
The results of the INTELLANCE 2 trial presented in November showed that those treated with Deputax-M in combination with temozolomide (TMZ) possibly did slightly better than those treated with just TMZ alone. However, these results were not significant enough.
The most recent results, presented at ASCO, include an additional few months of data and indicate that the difference in survival between the Depatux-M and TMZ combination versus TMZ alone is greater than originally shown.
The difference between the two treatments has increased as the data 'matures'. This means that those treated with Deputax-M and TMZ combination have shown better survival than those who were treated with TMZ alone and this difference shows up more over time.
Whilst the median overall survival shows a modest but significant increase from 8.2 months to 9.6 months, over 20% of those receiving the Deputax-M and TMZ combination survived over 2 years, compared to under 3% of those receiving just TMZ.
In addition, the Deputax-M and TMZ combination also performs very well in those individuals who have received TMZ more than 16 weeks prior to treatment. In these circumstances, median overall survival improves from approximately 10 months to 15 months.
However, because the INTELLANCE 2 trial had already been 'unblinded', meaning that the researchers and participants found out who took which treatment, the company cannot use these results to file for regulatory approval.
Fortunately, Abbvie are currently carrying out another clinical trial called INTELLANCE 1 that is testing Deputax-M in patients with a newly diagnosed glioblastoma. The results from this trial, if positive, can be used to file for approval from regulatory agencies.
These developments demonstrate the challenges faced by companies, as they have to balance the risk of reporting trial results too soon against the curiosity of understanding whether a treatment works.
Thankfully, in this case, Abbvie are making Deputax-M available through their compassionate use scheme, meaning that people this treatment. with a recurrent glioblastoma can speak to their clinician about accessing
Exwannabe,
Your quote:
“LP/NWBO hyped the PIMS designation. AF called BS. This board was citing PIMS as evidence of how good DCVax-L was,and calling AF an idiot for mocking it.
As time goes by, turns out NWBO never even follows up with the important work, getting the science reviewed. The PIMS designation was no more than a paperwork action. I wonder how many shares NWBO sold into that?
_______________________________________________________________________
Hmmm, strange statement for someone who follows this ihub board 24h/d.
We discussed this topic in the past few months! For clarity :first you have PIM (Promising Innovative Medicine) designation. At the end you have NICE Technology Appraisal.
See p.6 EAMS Schematic.
https://www.nice.org.uk/Media/Default/About/Who-we-are/Policies-and-procedures/eams-process-jan-16.pdf
“i. Promising Innovative Medicines (PIM) designation and NICE Topic Selection
– A PIM designation gives an early signal that, based on the evidence to date, the medicine may be a possible candidate for the Early Access to Medicines Scheme and thus has the potential to be of value in areas of unmet medical need. The MHRA operates the process resulting in a PIM designation.”
“vi. EAMS period and NICE TA or HST evaluation.
NICE anticipates that before the EAMS period starts, all EAMS products will already have been selected as topics for a NICE TA or HST evaluation.
In order to develop timely guidance, NICE starts the TA or HST evaluation during the EAMS period (before marketing authorisation), and the company prepares its submission during this period. Any data collected during the EAMS period may be included in the company submission.”
https://www.nwbio.com/first-uk-promising-innovative-medicine-designation-awarded/
"Linda Powers, CEO of Northwest Biotherapeutics Inc, said:
We are most grateful to the MHRA and Minister Freeman for spearheading this new Early Access to Medicines Scheme (EAMS). It strikes a very practical balance between clinical benefits and risks, through careful scientific evaluations, and will be of great help to doctors and patients in opening up new treatment options.
We are very excited to have DCVax-L receive the first designation under the EAMS, and believe that DCVax-L embodies the combination of innovation and beneficial balance of clinical benefits and risks that the EAMS is designed to accelerate."
JUNE 29,2018
Article: Combination of Immune Cells Improves Chances of Successful Immunotherapy.
“Krummel’s lab found a kind of immune cells called stimulatory dendritic cells (SDCs) were required for more robust T-cell responses. Without SDCs, T-cells were unable to respond effectively to checkpoint inhibitors.
However, for SDCs to be recruited and survive within tumors, another kind of immune cells was needed. Those are the NK (natural killer) cells, and usually act as first responders to detect cancer cells.
“One of the fascinating discoveries here is that we’ve long known that natural killer cells — as their name implies — can also kill cancer cells directly,” Krummel said. “But here we are discovering that their power doesn’t lie just in their ability to eliminate threats, but also in their ability to communicate with other immune cells.”
https://immuno-oncologynews.com/2018/06/29/combination-immune-cells-improves-immunotherapy-success/
Learn how the analysis of OS (overall survival) and PFS (progression-free survival) helps assess the potential benefit of Immuno-Oncology (I-O).
VuBru,
It was NOT trying to turn BAD news into GOOD news! It WAS trying to turn GOOD news into BAD news!
https://www.sec.gov/Archives/edgar/data/1072379/000114420415051646/v418946_ex99-2.htm
Shareholder Question:
There is a lot of confusion about your trial on the message boards. Are the 300 patients actually in the trial and being treated or are they just being screened? Also, what information are you submitting for regulatory review?
Company Answer:
Yes, the 300 patients are actually enrolled and being treated in the trial.
Also, being in the trial means that the patients are not in the Information Arm, and not in the pseudo-progression arm, each of which are parallel with the trial but outside the trial.
The supposed “confusion” about our enrollment is, once again, certain bloggers and commentators trying to turn good news into bad news about NW Bio and its trial. People familiar with clinical trials are generally aware that screening of patient candidates for eligibility is different than recruitment or enrollment of patients for treatment.
Regarding the information we are submitting for regulatory review: companies do not normally discuss such information when they are in the middle of a regulatory process or dialog, and we do not plan to do so either. We will provide an update when the process is finished and there is something to report.
The following information about the cost price of dcvax-l in the context of compassionate use in the UK was found on a blog called "Our brain tumor cocktails and stories".
The information is from 2015 and comes from a blogger Matjaz (30 December 2015) who had contacted the Company. I think this information is interesting in the context of RTT.
NOTE: it's in EUROS and British Pounds Sterling!
https://btcocktails.blogspot.com/2015/10/dcvax.html#comment-form
Matjaz30 December 2015 at 08:34
Please see the answer regarding costs from Ms. Carol Powers (I guess she is reponsible for public/patient relations) at NWBio:
DCVax-L is a labor intensive, custom-made vaccine based on the patient’s unique biomarkers, using the patient’s own dendritic cells. The vaccine is made in a "batch" manufacturing process, meaning the entire course of vaccine doses is manufactured at one time. In addition, DCVax-L must pass strict quality control standards before it can be released. The charges are as follows:
Total cost €53,000 (Euros) for the Tumor Lysate, DCVax Production and first 3 injections
• Deposit of €19,000 (Euros) due at time of Tumor Lysate production
• Balance of €34,000 (Euros) due at time of Leukapheresis processing
· Subsequent injections (injection 4 and following) cost €17,000 (Euros) each, due at the time of injection
• Leukapheresis costs range from $3,500 to $5,000 depending on the apheresis center and if a central line is required
· Initial consultation fee with UK physician £275 - £500 (British Pounds Sterling) * fees vary with the physician
• Shipping fees for tumor tissue, lysate, and DCVax-L are variable based on location but can be in the range of $1,200 to $1,800 or more
· VAT tax 20% - €10,600 (Euros) paid when the first three doses of vaccine are shipped
· Subsequent doses cost €17,000 (Euros) each and the VAT tax is 20% - €3,400 (Euros) paid prior to administration of the vaccine
• Physician’s charge for administering each dose of DCVax-L in the UK £1,125 - £1,500 * (British Pounds Sterling) * fees vary with the physician
Returning to work after multimodal treatment in glioblastoma patients.
Article (PDF Available) in Neurosurgical FOCUS 44(6):E17 · June 2018
OBJECTIVE:
Although multimodal treatment for glioblastoma (GBM) has resulted in longer survival, uncertainties exist regarding health-related quality of life and functional performance. Employment represents a useful functional end point and an indicator of social reintegration. The authors evaluated the rate of patients resuming their employment and the factors related to work capacity.
Discussion:
“GBM diagnosis and treatment has a significant socio-professional impact, with only a minority of patients being able to continue or resume their previous employment.
In our cohort, of the 125 patients who were working before their diagnosis, only 18.8% went back to work, most on a part-time basis”
https://www.researchgate.net/publication/325512535_Returning_to_work_after_multimodal_treatment_in_glioblastoma_patients
https://backend.otcmarkets.com/otcapi/company/financial-report/196848/content
h. The following is a complete list of Officers, Directors and Control Persons (control persons are beneficial owners of more than five percent (5%) of any class of the issuer’s equity securities), including name, address, and number of shares owned. Options and warrants that can be converted into common shares within the next 60 days should be included in the shareholdings listed below. If any of the beneficial shareholders are corporate entities, provide the name and address of the person(s) owning or controlling such corporate entities.
Name of Control Person Address (City and State only) Number of Shares
Owned
Alton Boynton, Ph.D Kingston, Washington Less than 1%
Marnix Bosch, Ph.D, M.B.A. Clyde Hill, Washington Less than 1%
Linda F. Powers Potomac, Maryland 1.97%
Leslie J. Goldman Chevy Chase, Maryland Less than 1%
Dr. Navid Malik London, United Kingdom Less than 1 %
Jeryy Jasinowski Washington, DC 1.31%
Date: 7-1-18
Name of Certifying CEO or CFO: Leslie J. Goldman
Title: Senior Vice President
Signature: */s/Leslie J. Goldman (Digital Signatures should appear as “/s/ [OFFICER NAME]”)
Flipper44,
On December 15, 2016, i believe doctor Linda Liau publicly announced that ending the DCVAX-L trial was absolutely no option and she had a good reason for this decision. The attentive listener was then aware that the trial would continue for a while!
I agree that it is an unorthodox approach to publicly announce a recommendation but I agree with Doc Logic that the playing field is often handicapped!
Quote Linda Liau:
“i guess one example of this is for instance we have a DCVAX clinical trial and which was designed several years ago and as part of the design we included a crossover arm because we felt that it was not necessarily fair to have patients randomized to treatment and and placebo and then not allow the placebo patients to at some point you know to get the vaccine ehm but but you know the at the end of the day what’s happenening is that the entire group is doing better at least you know it’s not unblinded yet i don’t know that where the groups live but both groups are doing better and it’s probably because the crossover arm those patients that got the DCVAX-L vaccine also saw some benefit so it’s it’s i personally think it’s great for patients that that both groups on on the clinical trial are doing better but unfortunately if the two groups don’t seperate in terms of how they’re doing we don’t get these drugs FDA approved and that’s that’s always a struggle you know you want to have the purest data is to get that placebo arm and prove it with definitive i guess evidence that something works but it’s really hard to withdraw you know with with old treatments from patients but when we try to combine the two unfortunately the i think that the regulatory don’t regulatory agents don’t necessarily understand that.”
Source: LIVE Q&A - Brain Tumor Treatments & Advancements
Seattle Science Foundation 24 Jan. 2017(published)
We were LIVE on Facebook with Charles Cobbs, MD, Director of the Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment and Linda Liau, MD, Director, Brain Tumor Program, UCLA School of Medicine taking all of your questions about brain tumor treatments & advancements.
Evaluate,
I think the key word is “centrally”.
Quote:
________________________________________
Randomization was performed centrally and was stratified by clinical site and MGMT (O6-methylguanine-DNA methyltransferase) gene promoter methylation status,
________________________________________
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6
Exactly!!!
But in the scientific publication you also see that patients were randomized 2:1!
“After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n?=?232) or temozolomide and placebo (n?=?99).”
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6
The question is why did Linda Liau make this slide public and why was it no longer available after the hold on recruitment was lifted by the FDA?
I think that this question has already been answered!
Flipper44,
I see 28 censors between the beginning of month 18 and month 23.1 timeline on the Overall Survival curve.
I see 14 of them on the Methylated curve and 14 of them on the Unmethylated curve between month 18 and month 23.1 timeline.
Flipper44,
I think you mean Dr. Stefaan Van Gool.
Article 05 April 2017: Star pediatric oncologist committed misconduct, ethical violations: reports
“ Since September 2015, Van Gool has been practicing at a clinic in Cologne, Germany and is still giving his experimental vaccine to patients, who must pay $45,000 or more for the three-course treatment”
https://retractionwatch.com/2017/04/05/star-pediatric-oncologist-committed-misconduct-ethical-violations-reports/
About Hospital Exemption: Form 10K-For the fiscal year ended December 31, 2017
“In March 2014, we received approval from the German regulatory authority of a “Hospital Exemption” for DCVax-L for glioma brain cancers under Section 4b of the German Drug Law outside of our Phase III trial. We undertook treatment of 9 patients under the Hospital Exemption. We did not undertake new Hospital Exemption patients while the Phase III trial enrollment was on partial hold. We do not plan to undertake further Hospital Exemption patients, as we are focused on completing the accumulation of data events, and analysis and reporting of the data, for the Phase III trial.”
https://www.sec.gov/Archives/edgar/data/1072379/000114420418020971/tv491101_10k.htm
Flipper44,
Linda Powers keeps repeating that all data remain blinded at the present. I think that means the last 32 patients included.
Quote:
“The data is to be viewed as preliminary for the time being,” explains Linda Power, CEO of the company behind the drug, Northwest Biotherapeutics, Inc. “The study is still ongoing and all of the data remain blinded at present.”
https://www.izi.fraunhofer.de/en/press/press-releases/manufacturing-immunotherapeutics-for-the-treatment-of-brain-tumors.html
Quote:
“The trial is ongoing while the data continue to mature, and the Company, the investigators and patients all remain blinded.”
https://www.nwbio.com/nwbio-announces-scientific-publication-interim-survival-data-phase-3-trial-dcvax-l-glioblastoma-brain-cancer/
From Fraunhofer IZI:
https://www.izi.fraunhofer.de/en/press/press-releases/manufacturing-immunotherapeutics-for-the-treatment-of-brain-tumors.html
Press release:
Manufacturing immunotherapeutics for the treatment of brain tumors – preliminary study results published
8.6.2018
Between 2011 and 2017, the Fraunhofer Institute for Cell Therapy and Immunology assisted American biotech company Northwest Biotherapeutics, Inc. in the conduct of a phase three clinical trial investigating the efficacy of the new DCVax®-L cell therapy in the treatment of glioblastomas. Fraunhofer IZI was responsible for preparing the investigational medicinal products for the European part of the trial. On May 29, 2018, the company published initial clinical findings in the Journal of Translational Medicine.
Before it could get up and running, in 2012 the Main Department of GMP Cell and Gene Therapy first had to transfer the GMP process for the DCVax®-L immunotherapeutic, which is based on autologous dendritic cells, and obtain the manufacturing authorization specifically required for this process pursuant to Section 13 of the German Drug Act (Arzneimittelgesetz, AMG). From this point on, the investigational medicinal products were manufactured in the clean rooms of Fraunhofer IZI in Leipzig for the European part of the trial, which covers study centers in Germany and the UK. The published results give reason to assume that the therapy is having a positive impact on patient survival rates, with the median overall survival time of the 331 patients examined increasing from an expected 15-17 months to an average of 23.1 months, and with 100 of the 331 patients showing median survival of 40.5 months. The personalized therapy also showed a good tolerability profile.
“The data is to be viewed as preliminary for the time being,” explains Linda Power, CEO of the company behind the drug, Northwest Biotherapeutics, Inc. “The study is still ongoing and all of the data remain blinded at present. The results may still change for the better or worse by the end of the study and following the final analysis. In view of the little progress made in treating glioblastomas over the past few years, these results are, however, encouraging.”
The autologous immunotherapy DCVax®-L is based on dendritic cells. These cells play a central role in regulating the immune system. As tumor tissue evolves from the body's own cells, it is often not recognized as foreign by the immune system and therefore not attacked. Through the DCVax® procedure, the dendritic cells are “educated” to recognize certain tumor antigens (biomarkers) which may only exist on the tumor cells. The modified cells subsequently stimulate T cells and additional mechanisms within the immune system to fight the respective tumor cells.
The original publication can be retrieved by following the link below.
Publication: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6
• Manufacturing immunotherapeutics for the treatment of brain tumors – preliminary study results published [ PDF 0.27 MB ]
Flipper44,
that was also my conclusion after reading the May 2018 publication. I have always believed that Linda Liau was very accurate in giving data. I believe that ALL placebo patients had progression in November 2016.At that moment all placebo patients had the possibility to get dcvax-L and I think that was the reason for the FDA to lift the hold. And remember, it was also the period that the Company started to communicate about the first endpoint and the promise that no more patients would be recruited! IMO
Umibe5690,
This is from your post 177160 Friday 06/08/2018:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=141418290
Quote:
“I believe in the science and I believe we are sitting on a pot of gold”
Any idea thanks to who?
Sentiment,
thank you for transcribing every testimony of the ASCO presentation!
https://twitter.com/KristynPower
Kristyn Power? @KristynPower 7 jun.
I'm unbelievably grateful to $NWBO for the treatment options offered to GBM patients. In addition to very encouraging interim results for patient survival, there are also significant quality of life advantages to their treatment. My Dad is the "60 year old man" in the article.
Larry Smith @SmithOnStocks
$NWBO Five Spectacular Patient Outcomes for Patients Treated with DCVax-L as Reported at ASCO See the report at this link. https://smithonstocks.com/northwest-biotherapeutics-five-spectacular-patient-outcome-for-patients-treated-with-dcvax-l-as-reported-at-asco-nwbo-0-28-buy/ …
And thanks for the attention for this article: Can Immunotherapy Succeed in Glioblastoma?
Subscribe May 24, 2018, by NCI Staff
This post was updated on June 6, 2018.
“Another vaccine, DCVax-L, is currently being tested in a phase III trial of patients with glioblastoma whose tumors could be removed surgically. DCVax-L is a dendritic cell vaccine, meaning it uses immune cells known as dendritic cells, which are collected from patients and engineered to provoke an immune response against multiple proteins, or antigens, on tumors.
Preliminary data from the trial were recently published, but only included survival data for the entire population of patients in the trial, not by treatment group. According to a statement from Northwest Biotherapeutics, which makes the vaccine and funded the trial, another round of data collection from the trial is ongoing.
Dr. Sampson’s team at Duke, which developed rindopepimut, has been testing a dendritic cell vaccine...…."
https://www.cancer.gov/news-events/cancer-currents-blog/2018/immunotherapy-glioblastoma
Flipper44,
Two days ago the expected publication date was 24 April 2019. Today it is 01 May 2019.
NICE moved the date only one week and not a month to 01 May 2019 for publication.
It is not that important but I see that someone is panicking.
News from NICE:
https://www.nice.org.uk/guidance/indevelopment/gid-ta10143
Timeline
Key events during the development of the guidance:
Date Update 14 June 2018 :Invitation to participate
https://www.nice.org.uk/guidance/gid-ta10143/documents/final-scope
https://www.nice.org.uk/guidance/gid-ta10143/documents/scope-consultation-comments-and-responses
https://www.nice.org.uk/guidance/gid-ta10143/documents/equality-impact-assessment-scoping
https://www.nice.org.uk/guidance/gid-ta10143/documents/final-matrix
Flipper44,
I'm sorry that I'm late with that whole package of censors
I've been very busy and have not had the time to reply. Now, I did what doctor Marnix Bosch asked to do, looked at the censors!
I THINK I can locate ALL THE CENSORS ON THE GRAPHICS OF ALL PATIENTS still alive at the time of the analysis of the blinded INTERIM DATA.(March 2017)
Censored patients are annotated by a small verticale line.
Note 1: it is my personal view of the figures but I think I am reasonably accurate. I have double checked them 3 times.
Note 2: that wonderful number is 108= patients still alive at the time of the analysis.(March 2017)
Note 3: The information comes from the paper,in particular from the Overall survival curve for patients in the intent-to-treat population and the curves of the ITT population stratified by MGMT gene promoter methylation status. (MGMT Methylated/Unmethylated) https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6
Title: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.
Note 4: to get the best result I used my glasses, a ruler, a notebook, a cell phone (mine is a Samsung AVII), a fine elastic that I wind around my cell phone.(it forms a movable line parallel to the y axis when I adjust the graph and scroll) and a bit of common sense.
Note 5: sometimes the censors are so close together that they form a thick censor, I call that a block. In that case you look at the
Methylated/Unmethylated curvers. In most cases a cursor is located on one curve and the other censor on the other curve and both on the same timeline.
Note 6: there are 10 blocks of 2 censors and 1 block of 3 censors.
They are located in the following places on the timeline:
-BLOCK 1 (2 censors): at the beginning of month 18.
-BLOCK 2 (2 censors): at the second half of month 19.
-BLOCK 3 (2 censors) at the second half of month 19
but one step down.
-BLOCK 4 (2 censors): at the first half of month 20.
-BLOCK 5 (2 censors): at the end of month 20.
-BLOCK 6 (2 censors): at the end of month 23.
-BLOCK 7 ( 2 censors with a little space in between and one step down) at the end of month 23.
-BLOCK 8 (2 censors): at the second half of month 25.
-BLOCK 9 (2 censors with a little space in between and one step down) at the end of month 25.
-BLOCK 10 (2 censors): at the end of month 26.
-BLOCK 11 (3 censors!!!): at the beginning of month 29.
Here are some (of many) of MY conclusions:
-I located 11 lost to follow-up patients, all on the left side of the month 18 timeline.
-I believe 2 patients were given surgery in late August or early September 2015. (the MEDIUM time from surgery to randomization was 3.1 months. For these last 2 patients the time from surgery to randomization was possibly 2 weeks below the medium)
-There are 28 censors between the beginning of month 18 and month 23.1 timeline.( NOTE: 23.1 months after surgery is the medium OS (mOS) for the intent-to-treat (ITT) population (n=331) at the time of the analysis (March 2017). These censors are all patients still alive at the moment of the analysis. (March 2017)
-There are 36 censors between month 23.1 and month 36 (End of the graphic). These censors are all patients still alive at the of the time of the analysis. (March 2017)
-Calculation of that wonderful number: 108 – 28 – 36 =44
-That means that every patient who ever crossed the month 36 timeline is still alive at the time of the analysis!
-There are 8 censors between month 23.1 and month 24. These are all patients still alive at the time of the analysis.(March 2017)
-At the time of the analysis(March 2017) 115 patients crossed the border of the month 24 timeline.
-From these 115 patients 44 crossed month 36 timeline and are still alive at the time of the analysis (March 2017). https://www.nwbio.com/dcvax-personalized-dendritic-cell-vaccines/
-From these 115 patients 7 are censored between month 30 timeline and month 36 timeline and are still alive at the time of the analysis.(March 2017)
-From these 115 patients 16 (67-7-44) patients lived at least 30 months but died before the 36 month timeline.
-From these 115 patients 21 (36-8-7) are censored between month 24 and month 30 and are still alive at the time of the analysis. (March 2017)
-From these 115 patients 27 (115-44-7-16-21) patients lived at least 24 months but died before the 30 month timeline.
-36(28+8) patients are censored between the beginning of month 18 and month 24 timeline and are still alive at the time of the analysis
-OVERVIEW EVERY TWO CONSECUTIVE MONTHS:
-15 patients are censored between month 18 and month 20 and are still alive at the time of the analysis.
- 9 patients are censored between month 20 and month 22 and are still alive at the time of the analysis.
-12 patients are censored between month 22 and month 24 and are still alive at the time of the analysis.
-10 patients are censored between month 24 and month 26 and are still alive at the time of the analysis.
-3 patients are censored between month 26 and month 28 and are still alive at the time of the analysis.
-8 patients are censored between month 28 and month 30 and are still alive at the time of the analysis.
-4 patients are censored between month 30 and month 32 and are still alive at the time of the analysis.
-2 patients are censored between month 32 and month 34 and are still alive at the time of the analysis.
-1 patients is censored between month 34 and month 36 and is still alive at the time of the analysis.
-With these figures in mind, the death event between month 24 and 26 and the 10 patients censored between month 24 and 26, I believe there is a population of extended survivors (n=100) that have lived at least 26 months with mOS of 40.5 months at the time of the analysis (March 2017).
-46 patients are censored between month 18 and month 26 and are still alive at the time of the analysis.
-I believe that all these figures are indicative of a long tail.
-I am convinced that all patients still alive are very,very, very thankful!!!
-I have tried to do my best.and I wish everyone good luck to find 1 more censor. Remember, the outcome must always be that wonderful number 108!!!!!
-I advise everyone to view the presentation of Dr. Marnix Bosch. (ASCO 2018) In my opinion, the last second of his presentation tells the whole story! https://www.nwbio.com/dcvax-personalized-dendritic-cell-vaccines/
-Best wishes
Marzan,
Maybe you can find :the “mystery of the hold” in these 2 PR. from the Company:
17 Sept 2013-https://www.nwbio.com/german-regulator-authorizes-nw-bios-phase-iii-gbm-trial-to-open/
Quote:
“We are excited to receive this rapid FINAL approval of our Phase III GBM trial from the German regulator,” commented Linda Powers, CEO of NW Bio.”
11 Aug 2014-https://www.nwbio.com/nw-bio-obtains-approvals-for-enhancements-of-phase-iii-trial-of-dcvax-l-for-gbm-brain-cancer/
Quote:
“The Company has obtained approval from the US FDA and the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and CONDITIONAL approval from the German regulatory authority (the Paul Ehrlich Institute, or PEI). The Company is now working toward the final approval from the PEI.
I wish you a nice weekend!
Flipper44,
I think that army of Zombies that is marching tot he right is also ignored!
Especially that army that has passed the 36-month limit. It must be somewhere, at least the moment when 108 patients were still alive. I think it is big and strong and well hidden!
From the computer screen.
Flipper44,
It is my way of looking at it. On the enlarged photo from the graphic i see 3 places where I count 4 censors in a row.
Flipper44,
I took a picture of the graph and counted the colored dark pixels. Maybe this is not the right way to do it, but I count 26 censor marks.(Start at the first vertical censor mark above the median (dashed line) and count all the way to the last two censor marks to the left of AVII's red line)
Flipper44,
I think this is NOTE (5) Beartrap 12 post 171261
Quote:
________________________________________
Me: PFS progression, did we find people who had not really progressed but because of pseudoprogression, were put down as having progressed?
Linda: I'm not sure where you're getting that from ...us going through this or that process.
We haven't said anything publicly about PFS or progression. We haven't talked about having gone through this process or that process. We haven't spoken about the subject yet. That's something will be... that lies ahead, that we will be speaking about in the future. But not that I'm aware of, we haven't spoken about it yet. So you have to stay tuned.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=140499659
Flipper44,
You wrote:
“Remember, one of the reasons I don't think there is likely much crossover impact in the current phase III trial (barring midstream manufacturing modification) is that the vaccine for crossovers will be based on the original tumor, not the recurrent and/or progressing tumor.)” (post 173725)
and you wrote:
-“Yes, hence why I see less chance for big crossover impact in the phase III trial (unless there was midstream optimization)”
-“(If there was a more potent version of DCVax-L created midstream, the more potent version might be able to help original placebos more. les is saying, apparently, off the record there was no midstream optimization in manufacturing.)” (post 173776)
But at the ASM ( 27 April 2018) Les Goldman give us the impression that everybody who is getting the vaccine is living longer! (See Notes 6 Beartrap12)
Quote:
“Les: I think its important for everyone following us, to take a step back and look and say, it can't be a bad thing if everybody getting the vaccine is living longer. So it becomes a question that with all the new policy initiatives at the FDA and overseas, how do our facts fit into this and as Linda says, it's still a work in progress to find the exact right slots, but the bottom line is if we have something where everyone who's had the vaccine is living longer, that's a pretty good thing. We shouldn't lose sight of this in the context of all the rules that used to be, and might be and are gonna be. People on the otherside of this would like to use that to camoflauge the reality of what may be unfolding.
Linda interjects “it's a maybe and we don't actually know for sure.”
Les: We don't know for sure.”
Flipper44, can you explain your point?
Thanks.
Flipper44,
I don’t know how important tangential flow filtration is but i saw these recent job description-Process Engineer-Gaithersburg, MD
posted : May 14, 2018 (Lentigen Technology Inc., a Miltenyi Biotec company)
Note: the ClinMACS devices are developed by Miltenyi Biotec company.
Experience Preferred:
"-Experienced in one, or both, of the following areas: o Bioreactor based production of biologics incorporating batch, fed-batch, or perfusion modes o Purification methods that include harvest clarification, chromatography, tangential flow filtration (TFF, UF/DF)."
https://recruiting.ultipro.com/MIL1021/JobBoard/f16cc611-8d8b-48fb-b086-24d10e2b6d21/OpportunityDetail?opportunityId=45317f5c-3319-4c42-993b-d029cf29c8b9
Sentiment,
I can not prove it, but I strongly believe that the Germans used a closed system for the manufacture of DCvax-L.
I learned that years ago (2012-2013) researchers from the Ghent University Hospital developed a new generation of DC vaccines and they used a completely closed system.
The Ghent University Hospital is located 25 miles from Brussels, the capital of Belgium and of Europe.
Note: Belgium is a neighbor of Germany and Ghent is 130 miles from Cologne (Germany).
Note:The production of the vaccine looks very similar to the production of Dcvax-L.
Some quotes from the Ghent Clinical Immunology, therapeutic & diagnostic platform:
“2011 also saw the birth of Ghent Clinical Immunology: a multidisciplinary platform supported by Ghent University Hospital, integrating clinically-oriented research efforts in the field of cellular immunotherapy and advanced immunological diagnostics.”
http://clinicalimmunology.ugent.be/page2/index.html
“the immunogenic power of the DC can be tamed to produce a cellular vaccine.
This concept opens unique opportunities for the treatment of cancer. Laboratories around the world have come to the same conclusion: cancerous growth can indeed be restrained by properly activated immune cells. Countless experiments have even demonstrated complete and selective eradication of cancer cells by the immune system.
With this knowledge, the idea was born to generate large amounts of dendritic cells from the blood of cancer patients, to activate these cells in vitro and to load them with extracts (“antigens”) from the patients’ tumor. This DC vaccine is then injected back into the patient. The aim is to have the activated DCs teach sufficient amount of killer lymphocytes to go seek and destroy cancer cells.”
“Thanks to support from Ghent University Hospital's “spearhead research initiatives”, the Foundation against Cancer, the Flemish League against Cancer and the IWT (Flemish agency for Innovation by Science and Technology), we are now developing a new generation of DC vaccines”.
http://clinicalimmunology.ugent.be/page10/page5/index.html
Below the page you find pictures how DC cancer vaccine prototypes were produced at Ghent University Hospital.
“The cells are run through the CliniMACS device, which uses magnetic fields to extract the monocytes in a completely closed system. The result is a cell bag containing 99% highly viable monocytes.”
About Fraunhofer IZI, first this comment: the building projects of the Fraunhofer IZI are sponsored 60 percent by the European Union and 20 percent each by the Federal Ministry of Education and Research and the Free State of Saxony. In the same manner, the expenses of about 11 million Euros for construction and equipment of the extension building were covered.( Fraunhofer IZI Annual Report 2014 P.167 )https://www.izi.fraunhofer.de/content/dam/izi/en/documents/Publications/Annual_Report_IZI_2014.pdf
I think Fraunhofer is the most valued research center in Europe!
Look at the equipment GMP Cell and Gene Therapy-IZI Fraunhofer. They have a CliniMACS Prodigy® device! (remember at Ghent University Hospital the cells were run through the CliniMACS device in a completely closed system).
https://www.izi.fraunhofer.de/en/departments/leipzig-location/gmp-cell-and-gene-therapy.html#tabpanel-3
Of course, i can not prove the Germans used a CliniMACS device to produce Dcvax-L!
More about CliniMACS Prodigy®:
The CliniMACS Prodigy® is a closed and automated platform with the capability to manufacture various cell types on a single device and within a single process setup. It delivers consistent product quality in every batch enabling reproducible cell production.
The closed system eliminates open processing steps and unnecessary operator transfers between multiple devices. Thereby, the contamination risk and associated quality variation from human intervention is significantly reduced.
https://www.miltenyibiotec.com/BE-en/products/cell-manufacturing-platform/clinimacs-prodigy.html
For me it seems very unlikely that the Germans used an open system to make the vaccine.
And on the other hand you also have the Hospital Exemption and the strict Regulatory notes!
For those who are interested in HE, you can find a lot of information in this Master Thesis, Dr. Anna Schnitger: The Hospital Exemption, a regulatory option for unauthorised ATMP's.
The Master Thesis is from 2014 but you will also find some information about Dcvax-L and HE.
http://dgra.de/media/pdf/studium/masterthesis/master_schnitger_a.pdf
Best Wishes!
Flipper44,
Perhaps you can find here one more indication of using a closed system in Germany: GMP Cell and Gene Therapy-IZI Fraunhofer- Eguipment- CliniMACS Prodigy®:
"The Department of GMP Cell and Gene Therapy operates Fraunhofer IZI's three modern GMP facilities consisting of ten separate clean room suites (altogether 21 clean room grade B manufacturing rooms) which have been specially optimized for manufacturing of cell and gene therapy products, so called Advanced Therapy Medicinal Products – ATMP. The particular specialty of the about 90 highly qualified staff members is the GMP-compliant manufacturing and quality control of investigational medicinal products. GMP-compliant process and quality control development as well as the creation of Standard Operating Procedures (SOPs) are intensively discussed with the project partner before being implemented. The leading staff in charge has many years of experience in designing GMP-processes in the cell therapy area."
https://www.izi.fraunhofer.de/en/departments/leipzig-location/gmp-cell-and-gene-therapy.html#tabpanel-1
Equipment:
Class A (100), B (100), C (10,000), and D (100,000) pharmaceutical clean rooms with a total area of about 1000 sqm, modular structure, divided into suites with separate air filtration. We offer altogether 21 class B manufacturing rooms within three separate clean room facilities for handling different kinds of manufacturing projects for cell and gene therapy products. If required the rooms can be operated according to gene technology safety level S2.
• Qualified equipment for the production of cell-based medicinal products, e.g. particle-monitored class II laminar flow workbenches, CO2-incubators (some with oxygen regulation), refrigerated centrifuges, inverse microscopes, controlled rate freezers for the cryopreservation of cells, storage tanks for storing cells in the vapor phase of liquid nitrogen, CliniMACS®-cell separation system, CliniMACS Prodigy®, LOVO-Cell Processing System, Sepax S-100-cell separation system, ELUTRA® cell separation system, gentleMACS™ Dissociator for tissue dissociation, TSCD II Sterile Tubing Welder, CR6 Tube sealers, etc.)
• Qualified equipment for the quality control of cell-based medicinal products (e.g. Cytomics™ FC500 MPL, FC500 Navios and MACSQuant® flow cytometer, LightCycler realtime-PCR-Cycler, Tecan Sunrise ELISA-Reader, Vi-CELL™ device for the automatic determination of cell count and viability, Sysmex XS-800i haematology system)
• Qualified equipment for sterility testing (BacT/Alert® 3 D Dual T-microbial detection system, Equinox-pump, overpressure isolator within clean room class C) and testing for bacterial endotoxins (Endosafe®-PTS™)
https://www.izi.fraunhofer.de/en/departments/leipzig-location/gmp-cell-and-gene-therapy.html#tabpanel-3
More about CliniMACS Prodigy®:
The CliniMACS Prodigy® is a closed and automated platform with the capability to manufacture various cell types on a single device and within a single process setup. It delivers consistent product quality in every batch enabling reproducible cell production.
The closed system eliminates open processing steps and unnecessary operator transfers between multiple devices. Thereby, the contamination risk and associated quality variation from human intervention is significantly reduced.
https://www.miltenyibiotec.com/BE-en/products/cell-manufacturing-platform/clinimacs-prodigy.html
Regulatory notes:
CliniMACS® Products
The CliniMACS System components, including Reagents, Tubing Sets, Instruments, and PBS/EDTA Buffer, are designed, manufactured and tested under a quality system certified to ISO 13485.
In the EU, the CliniMACS System components are available as CE-marked medical devices for their respective intended use, unless otherwise stated. The CliniMACS Reagents and Biotin Conjugates are intended for in vitro use only and are not designated for therapeutic use or direct infusion into patients. The CliniMACS Reagents in combination with the CliniMACS System are intended to separate human cells. Miltenyi Biotec as the manufacturer of the CliniMACS System does not give any recommendations regarding the use of separated cells for therapeutic purposes and does not make any claims regarding a clinical benefit. For the manufacturing and use of target cells in humans, the national legislation and regulations - e.g. for the EU the Directive 2004/23/EC ("human tissues and cells"), or the Directive 2002/98/EC ("human blood and blood components") - must be followed. Thus, any clinical application of the target cells is exclusively within the responsibility of the user of a CliniMACS System.
In the US, the CliniMACS CD34 Reagent System, including the CliniMACS Plus Instrument, CliniMACS CD34 Reagent, CliniMACS Tubing Sets TS and LS, and the CliniMACS PBS/EDTA Buffer, is FDA approved; all other products of the CliniMACS Product Line are available for use only under an approved Investigational New Drug (IND) application or Investigational Device Exemption (IDE).
CliniMACS MicroBeads are for research use only and not for human therapeutic or diagnostic use.
https://www.miltenyibiotec.com/BE-en/regulatory-notes.html
TOUCAN chose Kirsten Heukelbach as QA Manager at Advent Bioservices.
Kirsten Heukelbach
QA Manager at Advent Bioservices
United Kingdom
•
Dates Employed Jan 2018 – Present
Employment Duration 5 mos
•
“”Highly organized and experienced Pharmacy Production Manager with an in-depth understanding of pharmaceutical quality challenges and Good Manufacturing Practice (GMP). Manages operations supplying industry-leading services to pharmaceutical companies for Phase I and Phase II clinical trials from trial design through to report. Highly experienced in preparation of a wide variety of dose forms, sterile and non-sterile products, radiopharmaceuticals, repack/randomise/label IMPs, QP releases, controlled drugs and products for parenteral administration. Strong organisational and business acumen gained in working closely with trial sponsors and stakeholders at executive level, and in a multidisciplinary team commanding respect of medical, nursing, technical and administrative staff.
A fluent speaker of English and German and Graduate Pharmacist registered with the Royal Pharmaceutical Society and General Pharmaceutical Council of the UK with Master in Radiopharmaceuticals and PET Radiochemistry near completion.”
Experience:
Head of Pharmacy Production
Company Name Hammersmith Medicines Research Ltd
Dates Employed Aug 2005 – Jan 2018
Employment Duration 12 yrs 6 mos
Location London, United Kingdom
Maintaining and developing pharmacy services to achieve and maintain MHRA-licensed status. Directing, training, supervising and appraising staff. Developing and maintaining immaculate systems for documenting pharmacy procedures, to ensure compliance with Good Manufacturing Practice, managing the maintenance and performance-checking of pharmacy equipment, and ensuring it is serviced and calibrated as required.
Preparing IMPs, including sterile dose forms and radiopharmaceuticals, repackaging and relabelling of clinical trial supplies. Advising company and study sponsors on pharmacy work, and participating in meetings with them as necessary. Advising on and overseeing the purchasing of pharmacy equipment and materials, auditing suppliers and other third parties, as required. Writing and updating pharmacy standard operating procedure.
Advising the Medical Directors on the handling and administration of medicines, to maximise the safety of study subjects and company staff, and to minimise the likelihood of mistakes.
Training nursing and technical staff in pharmaceutical procedures, production issues and GMP principles, as necessary and appropriate.
Advising the Health and Safety Committee, and ward teams, on safe handling of materials.
Assessing safety data and writing COSHH assessments when necessary.
Liaising with pharmaceutical companies, other research laboratories and hospital departments.
Languages:
• English
• German
https://www.linkedin.com/in/kirsten-heukelbach-a2180425/
About Hammersmith Medicines Research Ltd
Pharmaceuticals London:
Specialists in clinical pharmacology phase 1 and early phase 2 trials.
https://www.hmrlondon.com/
Flipper44,
You wrote:
“It just seems the new obligations for reserving rooms with Advent (hello that's Toucan) at the empty arms hotel is just a reason to transfer shares from those with less knowledge, to those with more knowledge”
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=140916791
Maybe not so empty rooms!
Pilar Velasco Sevillano
GMP Production Scientist
Advent Bioservices
I.E.S. Benjamín Rua, Madrid
London, Greater London, Verenigd Koninkrijk
270 270 connecties
Hi!
I´ve participated in Spain in several clinical trials like a manager manufacturing to producing mesenchymal stem cells and mononuclear cells under GMP conditions, for implantation in hematology patients and like regenerative treatment in patients with acute myocardial infarction. I worked mainly with cell cultures at unit cell therapy, quality control, microbiological control and staining techniques.
Currently, I have started a fabulous project where I am going to be involved in performing dendritic cell culture as a treatment in oncology patients.
GMP production scientist
Advent Bioservices
sep. 2017 – may 2018: 9 months
London, Reino Unido
Performing dendritic cell culture as a treatment in oncology patients.
https://www.linkedin.com/in/pilar-velasco-sevillano-22026a55/
Best wishes!
Nice- Appraisal-DCVax-L for treating newly diagnosed glioblastoma [ID836]
New project lead: Kate Moore. (Before:Thomas Feist)
https://www.nice.org.uk/guidance/indevelopment/gid-ta10143
https://www.linkedin.com/in/kate-moore-03310213a/
Doc logic,
I wonder if you are talking here about a phenomenon, which alludes to the fact that immature dendritic cells (Dcvax-D) acquire immunogenic antigens from the tumor through the facilitation of tunneling nanotubes (TNTs) and thus supporting the concept of direct Ag transfer?
Sentiment,
Thank you for sharing that article. Fascinating learning material about Tunneling Nanotubes.
Quote:” The transfer of antigenic information from migratory DCs to lymph node-residing DCs through TNTs was recently shown to be critical for the induction of immune responses”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474251/
More about tunneling nanotube networks in dendritic cells in the following article:
“CD40L induces functional tunneling nanotube networks exclusively in dendritic cells programmed by mediators of type-1 immunity.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297732/