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No news about the dcvax-l trial in the latest Fraunhofer IZI annual report 2018. No English version yet.
https://www.izi.fraunhofer.de/content/dam/izi/de/documents/Publikationen/Jahresbericht_IZI_2018.pdf
Doc logic and Flipper44,
I think it is interesting to know that there is both a short version and a normal English version of the Fraunhofer IZI annual report 2017. The short version in particular is significant IMO.
SHORT VERSION 2017 P.27
PROJECT EXAMPLES
Manufacture of the immunotherapeutic DCVax®-L for brain tumor patients.
The manufacturing process for the immunotherapeutic DCVax®-L has been optimized and implemented as part of a clinical trial conducted by American biotech company Northwest Biotherapeutics, Inc. The therapeutic approach is based on autologous dendritic cells and aims to improve the treatment of glioblastoma, a particularly aggressive type of brain tumor.
https://www.izi.fraunhofer.de/content/dam/izi/en/documents/Publications/AnnualReport_IZI_2017_short.pdf
LONG VERSION 2017 P.28
PROJECT EXAMPLES
Manufacture of the immunotherapeutic DCVax®-L for brain tumor patients.
Until recently, Fraunhofer IZI spent several years manufacturing an investigational medicinal product for clinical trail in Germany and the UK, the efficacy of which is still being monitored as part of a phase III clinical trial.
American biotechnology company Northwest Biotherapeutics Inc. had previously succeeded in using the immunotherapeutic DCVax®-L in smaller clinical trials in the USA. This advanced therapy medicinal product (ATMP) is based on autologous dendritic cells and intended for the treatment of glioblastomas, a particularly aggressive type of brain tumor.
In order to manufacture DCVax®-L for each individual patient, tumor tissue and a blood product first had to be taken from the patient before the cell-based therapeutic agent could then be manufactured in a complex, multi-stage process. The number of patients that had to be recruited for the trial from a statistical perspective was reached back in 2015, marking the successful completion of the manufacturing and testing activities at Fraunhofer IZI.
However, as the therapeutic agent is being administered to the trial participants in several different doses over a threeyear period, cryopreserved clinical doses had to be sent to the participating clinical trail sites in 2017 for subsequent administration to the patients. This will also be the case in 2018, until the last scheduled dose is sent. We will then look forward to receiving the evaluation of the clinical trial from sponsor Northwest Biotherapeutics Inc.
https://www.izi.fraunhofer.de/content/dam/izi/en/documents/Publications/Annual_Report_IZI_2017.pdf
I do not know if this interview has been posted before and sorry if it was.
WINS Feature Interview with Dr. Linda Liau.(Fall 2018)
http://www.neurosurgerywins.org/wp-content/uploads/2018/10/2018-Fall-WINS-Newsletter.pdf
A respected Swiss Dr. who would like to collaborate with Linda Liau.
At the cutting edge of neurosurgery – A conversation with Dr Kienzler. September 1, 2018
We met with Dr Jenny Kienzler – who recently won the first prize from the Swiss Neurosurgical Society – to talk about some hot topics in neurosurgery. Dr Kienzler is a Swiss neurosurgeon based at the Kantonsspital Aarau. She was selected as research fellow at the Brain Tumor Center at the Department of Neurosurgery, University of California, Los Angeles, USA.
Brainwork: We hear you’re planning to move to LA in the near future! Will you be continuing this work there? What other research plans have you got?
Dr Kienzler: My project at UCLA is a 2-year fellowship with the broad aim of improving treatment of brain metastases, so it is not related to the ICP measurement device.
In essence, the clinical part of my work will involve the delineation of the best possible timepoint to perform radiosurgery, and how the timing of radiosurgery should be matched with the timing of immunotherapy. There is evidence that radiosurgery can activate the immune system, resulting in favourable outcomes after combining it with immunotherapy, so we would like to investigate this phenomenon. The laboratory-based part of my work will complement the clinical findings, as we will extract the immune and genetic profiles of various types of brain metastases and their primary tumours.
Brainwork: Are you moving to LA specifically for this work? What motivates you to move across the Atlantic?
Dr Kienzler: I will move specifically for this work – and I have done a lot of background research in deciding to go for this project. I wanted to work in an internationally renowned centre to specialize in Neuro-oncology and Stereotactic Radiosurgery. Meeting Dr. Linda Liau – the Chair of Neurosurgery at the David Geffen School of Medicine at UCLA – last year at the American Association of Neurological Surgeons (AANS) annual meeting was key to my decision. I was inspired by her and wanted to work with her, and the scope of her research matched very well with my interests.
My plan is to ultimately build my own research group in Switzerland whilst continuing to perform surgery. With respect to this goal, it is important to completely immerse myself in research for a time, to learn further techniques, and to broaden my horizons with new research questions. At UCLA, there are vast opportunities for collaboration between departments, so it is in many ways the right place for this type of project.
Brainwork: What advice would you give to someone else considering a similar move?
Dr Kienzler: I would say prepare yourself well in advance, and do plenty of background research on the type of project you are undertaking and the place you are going to. I have been preparing for this move for about three years.
I'm apparently becoming a rarer long that believes PFS probably succeeded.
Whereas the patients who developed systemic antitumor cytotoxicity had significantly longer survival than those who did not (P = 0.04), this survival difference also correlated with the presence or absence of tumor progression at the time of dendritic cell vaccination.
The development of a positive CTL response was negatively associated with active progressive disease (as measured by brain MRI). 100% (six of six) of patients who generated positive CTL responses had stable/minimal residual disease burden (stable gross residual disease or no measurable residual disease) at the time of dendritic cell vaccination. Conversely, for the five patients who were experiencing active tumor progression at the time of vaccination, none (zero of five) developed statistically significant cell-mediated CTL responses. These data suggest that glioblastoma multiforme patients with active tumor progression/recurrence may have an impaired ability to mount cellular antitumor immune responses, a finding that has been observed previously (33, 34).
Lykiri, why was the German lady almost certain that her husband was destined for the placebo group? She should have had no way of knowing that
I think LG was correct to imply these 31 patients were randomized appropriately. Maybe the "missing" 17 to fully enroll 348 were also randomized appropriately but were excluded from entering the trial.
Gus1212,
Thank You for the Laura Nuttall Update!
In terms of treatment, the monthly chemo is hitting her pretty hard but the recent scan does suggest that she may be responding to the treatment which is great news. We're having lots of conversations with the DCVax people and hopefully it won't be too long before we can update you with further news in that area.
Doc logic,
Thank you and i agree with you:
SOC/placebo enrollment seems to have been brought to an end on purpose
By the way, the fact that NWBO did not change direction back in 2014 to a greater emphasis on Direct convinced me that they were already pretty sure about DCVax-L. I think the Germans helped them make up their mind:).
Abeta,
Thanks for doing this! Good stuff!!
And thank you Flipper44, Smokey21, Doc logic and Barcode27( who brought the patent to our attention) for presenting it in such a clear format. Thank you all for your time and effort also!
For those who follow the story of the 19 year old Laura Nuttall diagnosed with Glioblastoma in the UK, an update (tweet from her mum):
Laura’s doing ok, her scan shows that the treatment is having an effect but she’s back on chemo again now so she’s horribly sick, it’s like snakes and ladders! We’re going to try to go ahead with the DCVax too if there’s enough tumour material to make the vaccine!
3:03 p.m. · 8 mrt. 2019
https://www.gofundme.com/ngdq37-doing-it-for-laura
https://www.bbc.com/news/av/health-46868801/student-makes-bucket-list-after-cancer-diagnosis
A courageous testimony:
Cancer crowdfunding 'couldn't save my daughter'.
By Melanie Newman and Jim Reed
BBC Victoria Derbyshire programme.
6 March 2019:https://www.bbc.com/news/health-47442946
.
I know that I can’t see the NOV 2018 slide well enough to make out the details of how many hash marks sit where. I know I see a hefty group right before the end, a couple more about a month back and then like one or two about 8 months back. So, I have to backwards deduce the numbers and guess.
Overview of Malignant Giloma: Management and Novel Therapies - Charles S. Cobbs, M.D.
14 Feb. 2019
4th Annual Innovative Approaches to Brain Tumor Management
• Friday, February 1, 2019
• 7:30 AM 4:20 PM
Agenda
12:10 p.m.
Immunotherapy for Brain Cancer (Working Lunch - Unaccredited)
Marnix L. Bosch, Ph.D., MBA
http://www.seattlesciencefoundation.org/events-calendar/braintumor2019
?????
Working Lunch- Marnix L. Bosch
12:10 p.m. Immunotherapy for Brain Cancer (Working Lunch – Unaccredited) Marnix L. Bosch, Ph.D., MBA
Objectives: At the conclusion of this presentation, attendees will provide better patient care through an increased ability to:
• Discuss how the immune system can be mobilized to attack cancer
• Explain what specific immune mechanisms are important specifically for brain tumors
• Describe what are avenues for optimizing anti-brain tumor immune therapies
https://static1.squarespace.com/static/554037b3e4b0da169013a32f/t/5c51dfdc7924e84a7f3135e9/1548869596351/Brain+Tumor+Agenda+2019.pdf
Two things to note. 1) FDA was really fooled by the early PFS responders doing poorer than the control thus PFS faked out FDA to initiate the hold in 2015, imo. Those two charts PFS and OS that Carlo gave make perfect sense. And the late PFS line performs way better than the control was the waiting time bet 2015 and 2017 for FDA to see and lift the Hold. And so is now LP says there was a hostile takeover and much more that they struggled to sustain and on. 2) AF says lysing the tumor that has neoantigens and pulse it with DC won't wok but needs a special T cell engineering - what the heck is he talking about. Bigger et al are laughing at him. Where did Carlo get the PFS chart?
Fraunhofer seems to like the thought they optimized manufacturing during the second half of the trial. That might account for the eventual increase in three year survival.
Manufacture of the immunotherapeutic DCVax®-L for brain tumor patients.
The US biotechnology company Northwest Biotherapeutics Inc. is conducting a phase III clinical trial in Europe to examine the efficacy of its immunotherapeutic DCVax®-L, whereby the Fraunhofer IZI is responsible for manufacturing the investigational medicinal products. DCVax®-L is an advanced therapy medicinal product (ATMP) based on autologous dendritic cells to treat glioblastomas, a particularly aggressive type of brain tumor.
After the clinical trial was approved in the UK and following capacity increases at the Fraunhofer IZI (concerning clean rooms and staff), patient batches for use in British hospitals have been produced since June 2013. In addition, both the clinical trial and a special permit pursuant to Section 4b AMG (”hospital exemption”) were authorized by the Paul Ehrlich Institute. The authorization pursuant to Section 4b AMG permits the manufacture of advanced therapy medicinal products as an individual preparation for individual patients who are not able to be included in a clinical trial due to their indication or other exclusion criteria. Batches for German patients have been manufactured in the clean rooms and administered to patients as part of the clinical trial since August 2014; patient batches for treatment pursuant to Section 4b AMG have been manufactured and administered to patients since October 2014.
Manufacture of the immunotherapeutic product DCVax®-L for brain tumor patients.
Fraunhofer IZI is producing and optimizing an investigational medicinal product in Europe, the efficacy of which is currently being investigated as part of a phase III clinical trial. American biotechnology company Northwest Biotherapeutics Inc. has already successfully used the immunotherapeutic product DCVax®-L in clinical trials in the US. This advanced therapy medicinal product (ATMP) is based on autologous dendritic cells for the treatment of glioblastomas, a particularly aggressive type of brain tumor
Furthermore, applications to conduct respective clinical trials were submitted to the responsible authorities in the United Kingdom and Germany and initially authorized in the UK. Consequently, in June 2013, production commenced for the treatment of patients there. Authorization of the trial in Germany the following year then also gave the green light for the production of batches for German patients, which has been ongoing since August 2014
Comments on twitter from Sean Sachdev, MD on Lomustine-temozolomide study.
I recall presented at SNO2017. Some issues: small numbers ~130 pts & imbalance; survival estimate comes from a stratified analysis & they used "inverse probability weights." With the pure unstratified analysis 31.4/37.9 (p=0.66) not statistically significant. Intriguing though.
Comments on twitter from Craig Horbinski on:
"Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG / NOA-09): a randomized, open-label, phase 3 trial."
A key to the potential success of this trial (Sean's wise observations taken into consideration) was the fact that they combined two cytotoxic drugs AT THE TIME OF INITIAL DIAGNOSIS. Hit 'em as hard as possible upfront!
survivor1x,
Thanks,
Detection of immune responses after immunotherapy in glioblastoma using PET and MRI.
Joseph P. Antonios, Horacio Soto, Richard G. Everson, Diana L. Moughon, Anthony C. Wang, Joey Orpilla, Caius Radu, Benjamin M. Ellingson, Jason T. Lee, Timothy Cloughesy, Michael E. Phelps, Johannes Czernin, Linda M. Liau, and Robert M. Prins
PNAS published ahead of print September 5, 2017 https://doi.org/10.1073/pnas.1706689114
The inability to accurately monitor glioblastoma tumor progression vs. pseudoprogression has severely limited clinical treatment decisions, especially in the setting of immunotherapy. We have identified a novel noninvasive imaging combination that could distinguish intracranial immune responses from tumor progression in mice bearing orthotopic gliomas and in patients with glioblastomas. We combined the use of advanced MRI with PET imaging of deoxycytidine kinase, an enzyme overexpressed in immune cells. This combination resulted in superior differentiation between immune responses and tumors within the brain, and identified peripheral lymph nodes in which immune responses occurred after immunotherapy combinations. This combined imaging approach may provide a useful method to clinically monitor patients with glioblastomas treated with immune-based therapies, and to distinguish tumor progression from pseudoprogression.
AVII77,
Thanks,
So, what do you do if you have a SOC patient who progressed, crossed over and received dcvax, and then it turns out the tumor regressed (psPD).
Was that regression due to DCVax on x-over or due to psPD from SOC (we know SOC causes psPD, we don't know if DCVax causes psPD).
How do you handle that? You can't suck the dcvax out of him.
My dad is in the DC Vax L trial and just started the cross over arm about 2 weeks ago. He's received 2 injections so far and 1 next week since he's been in the cross over arm.
He started the trial around a year ago and was crossed over 2 weeks ago due to progression. At first Drs thought it was scar tissue but after 3 mris (6 month time frame), it became more clear it was slow tumor growth.
AVII77,
Thanks!
It was more in the sense of cross-over.
Almost 90% of patients have received DCVax-L at some point. -67% received it at randomization, and the rest received DCVax-L after documented disease progression.
AVII77,
NWBO speaks of "documented disease progression".
Can you make something of that?
Global Anti-PD-(L)1 4Q18 sales:
$MRK Keytruda $2151M (+66% YoY)
$BMY Opdivo $1804M (+33%)
Ono Opdivo $235M (+3%)
$AZN Imfinzi $262M
$RHHBY Tecentriq $248M (+89%)
$REGN Libtayo $15M
$PFE Bavencio N/A
Total class at ~$19B run rate, that's >15% of global drug spending on oncology!
https://pbs.twimg.com/media/DzcyJMDWsAES0ZV.png
The lomustine crisis: awareness and impact of the 1500% price hike.
Neuro-Oncology, Volume 21, Issue 1, 1 January 2019, Pages 1–3, https://doi.org/10.1093/neuonc/noy189
Published: 22 December 2018
Lomustine was marketed by Bristol-Myers Squibb as CeeNU until 2013. At that time it was sold to NextSource Biotechology, a leading specialty pharmaceutical manufacturer and was re-branded as Gleostine. This is currently the only company producing lomustine in the United States. Since 2013, we have seen the cost of lomustine increase by >1500% from $50 to $768 per capsule.
What does this story -Iovance Biotherapeutics and lifileucel (LN-145)- tell us about the current FDA policy?
As the company moves forward to potential regulatory approval of a potential solid tumor cell therapy, Fardis said her team has also been working to improve the manufacturing process to ensure the asset is available for the patient when it is time for commercialization. Iovance has improved the manufacturing process of its TIL products.
Fardis said the company has shortened the manufacturing process of a frozen product to 22 days. That will provide the therapy with a longer shelf life if the patient is not ready to receive the treatment, she said. With potential commercial manufacturing of the company’s TIL products looming, Fardis said she was excited to move toward the manufacture of their own products.
The FDA granted Fast Track designation for LN-144 for metastatic melanoma. Since the designation was awarded, Fardis said the company has been working hard to hit the mark, particularly since the regulatory agency provided the company with some incentivized news during an end-of-phase meeting. During that meeting, the FDA said a single arm cohort of the C-144-01 study could be supportive of initial registration for lifileucel, which means that conducting a randomized Phase III trial in the patient population may not be necessary. The FDA also received the FDA’s Regenerative Medicine Advanced Therapy (RMAT) designation for lifileucel.
There's a 2nd GBM paper from Ignacio Melero's group too:
Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma.
Published: 11 February 2019
Abstract
Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3?cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
https://www.nature.com/articles/s41591-018-0339-5
Longfellow95,
I don't know if these subjects received Bev because that caps survival after recurrence at 9 or 10 months...
“This isn’t a very big study, and our data need to be replicated, but we have a foot in the door,” Cloughesy said. “We have found a way to use these checkpoint inhibitors in glioblastoma that we previously thought were ineffective. We now have a rational and logical way to develop immunotherapies going forward and a clinical development process for doing it.”
The team is now testing the immunotherapy in combination with vaccines and other checkpoint inhibitors.
Meirluc,
I agree.
Dr.Bosch was very accurate with that number of approx. 100 patients alive.(ASCO 2017)
Look at the latest OS curve of 2018 (SNO) and locate all recent step downs.
When you have found them all, you will notice that approx. 100 was not exaggerated. (It was not 85 or 95 or 105 IMO)
Longfellow95,
Does such a patient actually start getting a placebo dose after all their treatment doses are exhausted?
Doingmybest,
In my opinion the LTFU patients are included in the 231 OS events.
It is written this way:
Approx. 100 patients still alive (231 OS events; a few lost to follow up)
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=146656089
Look at the punctuation mark; semicolon.
Semicolon
From Wikipedia, the free encyclopedia:
The semicolon or semi colon[1] (;) is a punctuation mark that separates major sentence elements. A semicolon can be used between two closely related independent clauses, provided they are not already joined by a coordinating conjunction.
In my opinion, Dr.Bosch included those LTFU patients in the 231 OS events by using a semicolon.
Sander,
Friday, 01/04/19 05:30:25 PM
You wrote:
I do not have any position in NWBO long or short.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=145890678
Jack2479,
Thanks for the update!
Thanks Ike, excellent job well done!!
Longfellow95,
I have the impression that Linda Powers was not worried about the first endpoint (PFS) at the time.
May 7 – 2015 Linda Powers:
So four months difference is all we have to show in the phase three trial, and if we show that much of a difference, we will have a very strong p-value of .02. The trial is also powered for the secondary endpoint of overall survival, and as you see here, multiple subgroup analyses were prospectively included. There are a number of subgroups, certainly MGMT status is one of them; there are several others. In fact, MGMT status, which is a gene that effects chemo therapy sensitivity… that’s part of standard of care… to the chemotherapy, is included in the actual randomization of the patients. So it’s taken into account in the formula under which patients are randomized. So they’re even randomized for these factors. Again, that trial is due to finish around the summer of next year to reach the primary endpoint, and we are certainly looking forward to that.
Once he was well enough Adrian flew back to London where he was treated by Paul Mulholland, the oncologist who was also treating Nicki Waterman, who was a celebrity fitness trainer and columnist for The Sun newspaper. Like Nicki, Adrian’s tumour was a glioblastoma multiforme (GBM), the worst possible type. It was cancerous and aggressive. With no clinical trials available, Adrian took the decision to self-fund a course of DCVax®, a pioneering new type of immunotherapy treatment. Cells from Adrian’s excised tumour were used to create a vaccine using activated dendritic cells, the master cells of the immune system.
After that, I recall that LP said in a PR something to the effect of 'we will be doing an efficacy analysis later in the year' but for the life of me, I can't find that reference now.
In terms of the interim analysis, it would be likely to be this year, potentially in the coming months." Minutes 26'10 of the VirtualInvestorConference Webcast.
So...
the Germans read that they are moving toward trial completion that has been going on for months,
versus
the Americans read that they are moving forward with months of work towards trial completion.
"Nun, da die Daten aus unserer klinischen Phase-III-Studie mit DCVax®-L weiter gereift sind und ein weiteres ermutigendes Bild für den Überlebensvorteil für Patienten liefern, und wir bereit sind, die monatelangen Arbeiten zum Abschluss der Studie fortzusetzen, freuen wir uns sehr, neue Rücklagen für diese Arbeit zu haben", kommentierte Linda Powers, CEO von NW Bio. "Wir freuen uns auch darauf, weitere DCVax®-Direct-Studien durchzuführen."