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Dendream, I think you left one of the biggest tells off that list:
Would you . . . continue to use a treatment for compassionate use, if it failed in its clinical trial?
Right ATLnsider, looks like that is the only one revived?
HEALTHBANK
Filed: June 4, 2021
immune cells, namely, cells for medical or veterinary use; tissue cells, namely, cells for medical or veterinary use; biological…
Owned by: Linda F. Powers
Serial Number: 90755320
VET-BANK
collection, processing and preserving of biological cells, tissues, and derivatives thereof for others, for veterinary,…
Owned by: Powers, Linda F.
Serial Number: 78888413
THE FUTURE OF CANCER MEDICINE.... NOW
biological research; biotechnology research; medical and scientific research in the field of cancer treatment and diagnosis…
Owned by: Powers, Linda F.
Serial Number: 86156447
STORING LIFE
collection, processing and preserving of biological cells, tissues, and derivatives thereof for others, for veterinary,…
Owned by: Powers, Linda F.
Serial Number: 77345147
PRESERVING LIFE
collection, processing and preserving of biological cells, tissues, and derivatives thereof for others, for veterinary,…
Owned by: Powers, Linda F.
Serial Number: 77345154
PRESERVING LIFE FOR HEALTH
collection, processing and preserving of biological cells, tissues, and derivatives thereof for others, for veterinary,…
Owned by: Powers, Linda F.
Serial Number: 77345157
STORING LIFE FOR HEALTH
collection, processing and preserving of biological cells, tissues, and derivatives thereof for others, for veterinary,…
Owned by: Powers, Linda F.
Serial Number: 77345149
STORING LIFE FOR HEALTHY TOMORROWS
collection, processing and preserving of biological cells, tissues, and derivatives thereof for others, for veterinary,…
Owned by: Powers, Linda F.
Serial Number: 77345751
PRESERVING LIFE FOR HEALTHY TOMORROWS
collection, processing and preserving of biological cells, tissues, and derivatives thereof for others, for veterinary,…
Owned by: Powers, Linda F.
Serial Number: 77345759
STORING LIFE. RESTORING HEALTH.
collection, processing and preserving of biological cells, tissues, and derivatives thereof for others, for veterinary,…
Owned by: Powers, Linda F.
Serial Number: 77361358
The Lindas were ahead of their time, and have been talking about freezing tumor tissue for over a decade. Back then, the idea was relatively novel, and since there was a lack of understanding of the need for molecular profiling, and there weren’t any personalized medicines, to most neurosurgeons and hospitals, it seemed unnecessary. Things have changed since then, and like the recent increased awareness and rationale for using external control arms in rare diseases, so too is awareness of the need for new standards and tissue banking.
Here’s an old article where the two Lindas are quoted:
Patients, hospitals wrestle over tumor tissue
By Stacey Burling August 2, 2010
HILADELPHIA — All Niki Perry wanted was pieces of her own brain, and she got angrier by the day as she tried to get them. She needed samples of her brain tumor this spring to enter clinical trials she hoped might save her life.
What she got, she said, was delay and disappointment. Plus insight into what she sees as a new battleground: who controls what happens to tiny bits of tumor tissue saved after surgery. This tissue is growing more precious as scientists unlock its potential to target treatments to a specific person’s cancer.
When Perry had surgery in September, she knew better than most patients how valuable the deadly cells in her tumor might be someday.
A frequent participant in brain-cancer message boards and an aficionado of new research, Perry knew she might want to enter a European cancer vaccine clinical trial or seek genetic testing that would require frozen pieces of her tumor. She said she asked her surgeon at Thomas Jefferson University Hospital to freeze some just in case.
Freezing tumor cells in a form that can be used for vaccines or advanced genetic testing is unusual. Doctors always put some of the tumor, preserved in formalin and embedded in wax, in slides and small blocks for diagnosis and later testing. Perry knew she would want that, too.
When in March she requested the frozen tissue and her slides, Perry said she ran into weeks of red tape and a Catch-22. She says Jefferson balked at sending slides to another hospital until she was officially in a trial there. But she needed the tissue to enter the trial. Jefferson finally mailed the slides at the end of May and she picked up the tissue blocks herself at the hospital. To her dismay, she learned there was no frozen tissue.
The 37-year-old South Philadelphia woman, who has had speech problems since the surgery and now communicates more easily by e-mail, wrote that she felt “helpless” and “enraged” as she fought for the tissue. She felt the hospital, which has said it will not comment on her individual case, got “in the way of my trying to save my own life.”
Cancer surgeons at Jefferson usually do not freeze tumor tissue, and Peter McCue, who runs Jefferson’s anatomic pathology laboratory, said he did not receive instructions to save frozen cells. He said Perry should not have had trouble getting slides.
Perry’s experience is unusual, but she says she’s seeing more complaints on message boards from patients having trouble getting tissue sent from one hospital to another.
Some doctors agree with her. They say problems with tissue-sharing likely will worsen as the era of “personalized” cancer treatment unfolds. Individualized care is spurring higher demand for tissue, creating nascent tensions between research and treatment. That’s making tumor cells a hot commodity, one that patients — bewildered and terrified by a life-threatening diagnosis — often give little thought.
Cancer treatment protocols already contain acronyms for biomarkers — HER2, EGFR, KRAS — that determine which drugs will be used. Memorial Sloan-Kettering Cancer Center does genetic profiling of most of its lung-cancer cases. Swedish Medical Center in Seattle routinely profiles brain tumors.
This is where cancer treatment is heading. The trend has huge fiscal, medical, and social implications. Instead of everyone getting the same chemo cocktail, patients will get treatments aimed at specific mutations in their cancer. They can avoid side effects from drugs that won’t help them and can avoid paying for expensive treatments that won’t work.
Gregory Foltz, a neurosurgeon who directs brain-tumor treatment at Swedish, says genetic profiling done with frozen brain-tumor tissue may identify the most aggressive forms of a disease that can kill in months. That will help patients make key decisions, like whether to quit a job or enroll in a riskier trial. Companies can justify drugs with smaller target markets. One lung-cancer treatment in development, for example, seems to work well, but only for 3 percent of patients.
Tumor tissue is the keystone of the new science, and its use is fraught with complex, unanswered questions. When cancer patients have surgery, they usually sign consent forms allowing their tumor to be used for research, although hospitals say patient needs should trump science. Tumor tissue might not only save a patient’s life — or the lives of other patients years later — but reveal scary genetic truths about him, his family, or his ethnic group. You can’t legally sell tissue itself, but its secrets might help a drug company make millions.
So who really owns this stuff and has the right to make decisions about it?
You might think the obvious answer is the patient. But that’s actually not clear. C. Mitchell Goldman, a health care lawyer at Duane Morris L.L.P., expects more lawsuits as more uses for tissue emerge.
“There’s not a body of settled law around this issue,” he said. It’s “fertile for litigation once it becomes clear that having control of this tissue for future use will become important.”
Penn bioethicist Arthur Caplan thinks hospitals will have to reserve more tissue for patient use.
“The notion of ‘I-might-want-it-myself’ has just emerged in the last few years,” he said. “There’s no point in having personalized medicine and mapping the genome if you can’t get your tissues shipped.”
The evolving problem is that doctors and researchers need more tissue now, and in new forms, while there may be less of it. Early detection and needle biopsies have shrunk the size of tumor samples in some diseases, notably breast cancer. Even though brain tumors like Perry’s may be large, surgical techniques often yield little usable tissue.
Doctors are doing more tests on tumors, both before and after treatment. In some trials, they’re using live tumor cells to make medicines or profile genes. Academic centers such as Hospital of the University of Pennsylvania are augmenting their diagnostic tissue banks with new frozen repositories earmarked for research. Penn’s costs $250,000 to $300,000 a year to maintain, said Michael Feldman, a pathologist who runs the new program.
Carolyn Compton, director of the National Cancer Institute’s office of biorepository and biospecimen research, said sharing is suffering. Trouble acquiring tissue, she said, is one of “the most common and pervasive issues” in NCI-sponsored clinical trials. The percentage of tissue that researchers can get from other hospitals has gone from 90 to 75 or 80 and it’s still falling.
“There’s been a growing difficulty,” Compton said, “in getting those tumor samples out of the institution where the patient had their surgery.”
Frozen tissue used for immune therapies like the one Perry wanted is especially challenging. It must be sterile and stored in a way that preserves cell viability. This is very expensive. Even research powerhouses like Penn usually don’t freeze tissue that way.
Plus, sharing is impractical because different trials use different freezing methods, said David Berd, who is testing an ovarian cancer vaccine at Cancer Treatment Centers of America.
The bottom line, researchers said, is that patients who want vaccines that use frozen tissue either have to have surgery in a hospital that’s doing the clinical trial or they have to ask for special treatment before the operation.
That’s asking a lot of patients. “They’re in a state of shock and they get rushed into surgery right away before they hardly know what hit them,” said Linda Powers, an owner of Northwest Biotherapeutics, a Bethesda, Md., company that’s testing a brain-cancer vaccine.
George Coukos, ovarian cancer research director at Hospital of the University of Pennsylvania, wants to create a regional bank to store specially treated fresh cancer tissue. He needs it for two new immune-therapy trials.
After the need for tissue slowed recruitment to Northwest’s trials, Powers set up HealthBank, a private frozen-tissue bank where patients pay to store their own tissue — if they can convince their surgeon to help.
Since tissue banking began a few months ago, two hospitals have refused to participate.
“Their policy was that it was their material to use,” Powers said. “Once it comes out of the patient in their institution, it belongs to them, not to the patient.”
While some cancer experts think private banks might help, others were critical.
“These things are not regulated. There are no standards. It’s the Wild West,” Compton said. “Until this is all standardized and regulated, I’d say you’re just throwing your money away.”
There’s another Catch-22. Pathologists, who are required to keep tumor samples for several years, are increasingly worried about releasing tissue that might be needed later for new treatments, Compton said. Meanwhile, development of those treatments hinges on tissue.
Jefferson’s McCue thinks researchers hungry for tissue increasingly are asking for samples as the “ticket” into clinical trials, even though they’re not really essential.
Patients don’t realize how small the samples are. Years from now, when a more promising trial starts, McCue doesn’t want to have to say there’s nothing left. Then “we’ve blown our stake at the poker table,” he said.
Should cancer patients consider all this when they have surgery? Most doctors think that’s unrealistic.
“Hopefully, as we move more toward personalized medicine, the medical community will think about it so patients don’t have to,” said Linda Liau, a neurosurgeon who directs UCLA’s brain-tumor program.
Perry is still steaming over avenues now blocked because there is no frozen tissue.
“I am utterly crushed by not having access to what I truly believe is the best, most amazing trial ever,” she said, referring to a vaccine trial in Belgium. The trial that needed her slides rejected her because her cancer had spread.
She’s weighing less-appealing alternatives now. “I’m totally freaking out day after day,” she said, “desperately digging for something that holds promise.”
Stacey Burling
https://www.seattletimes.com/seattle-news/health/patients-hospitals-wrestle-over-tumor-tissue/
I get your point Basin. The vast majority of current NWBO shareholders are small retail investors with little knowledge about proper valuations, outstanding shares, warrant expirations, debt conversions, or even most of the scientific discussions on this board. I’ve often wondered about their commitment post data release, but I agree that there will be many more that want to get in than want to get out. We did see tens of millions of shares traded last October with very little public news, so I’m pretty confident that on the OTC, things will likely get pretty crazy when we get potentially ground breaking news blasted worldwide and the dam finally breaks . . . #CULT STOCK?
Thanks VuBru, appreciate your perspective - again.
Right antihama, one tick out of how many? (keep scrolling)
GMP checklist for ATMP manufacturers
https://atmpsweden.se/wp-content/uploads/2019/05/Guide-GMP-checklist-1.0.pdf
Well ATLnsider, it seems to me that the best way to handle the logistical issues with a cell therapy is to first remove any time constraints by cryopreserving the leukapheresis material, which I’m pretty sure will be the case. I’ve posted before that I think it makes sense to have regional manufacturing regardless, so when the time comes for commercial manufacturing, I believe Northwest Bio will contract with Advent at Sawston to manufacture for the UK and EU, while Charles Rivers Labs will manufacture for the US and Canada. The closest model that I know of for the commercialization of a cell therapy is KITE/Gilead, and that’s exactly what they did (regional manufacturing) even with cryopreserved leukapheresis material.
I’m not sure if anyone else noticed this language in the latest Q:
Manufacturing Services Agreements
Advent BioServices
On November 8, 2019, the Company and Advent entered into an Ancillary Services Agreement with an 8-month Term for U.K. Facility Development Activities and Compassionate Use Program Activities. The Ancillary Services Agreement establishes a structure under which Advent develops Statements of Work (“SOWs”) for the U.K. Facility Development Activities and Compassionate Use Program Activities, and delivers those SOWs to the Company for review and approval. After an SOW is approved by the Company, Advent will proceed with or continue the applicable services and will invoice the Company pursuant to the SOW. Since both the U.K. Facility Development and the Compassionate Use Program involve pioneering and uncertainties in most aspects, the invoicing under the Ancillary Services Agreement is on the basis of costs incurred plus fifteen percent. The Ancillary Services Agreement had an original term of eight months, which ended in July 2020. The Company extended the term by 12 months to July 2021, with no other changes, and recently extended it for another 12 months to July 2022.
Wow, impressive!...but how did you ever get the name BigAl?
During the approval process for new marketing applications, the FDA conducts inspections and assessments of all facilities (worldwide) wherever a drug is manufactured, processed, and packaged to determine a drug manufacturers’ compliance with CGMPs, applicable laws and regulations, and to determine whether the firm has the necessary facilities, equipment, and ability to manufacture the drug it intends to market. There are Mutual Recognition Agreements (MRAs) between the FDA and foreign regulatory authorities which allow drug inspectors to rely upon information from drug inspections conducted within each other’s borders, however, Advanced Therapy Medicinal Products (ATMPs) are excluded from the scope.
Facts About the Current Good Manufacturing Practices (CGMPs)
https://www.fda.gov/drugs/pharmaceutical-quality-resources/facts-about-current-good-manufacturing-practices-cgmps
Northwest Bio has said that the monocytes should arrive at their manufacturing facility within 24 hours to remain viable for the manufacturing of DCVax, but generally fresh monocytes remain viable for 24 to 48 hours. I posted about this not too long ago:
With fresh monocytes, there’s a limited window (24-48 hours) in which manufacturing should take place because cell viability decreases after that time. Therefore, manufacturing timeslots have to be reserved for each patient prior to undergoing leukapheresis. This presents logistical challenges if there are shipping delays, or if sick patients miss their leukapheresis appointment, which can cause cancelled manufacturing slots and rescheduling backlogs. During the trial, there were only a few hundred patients treated over many years, so these issues could be overcome fairly easily. But this becomes a nightmare for commercial manufacturing when hundreds of patients a month from all over the country are being scheduled. The solution is to cryopreserve the leukapheresis material, which not only provides scheduling flexibility, but also allows centralized manufacturing from a greater distance. Unfortunately, this requires comparability studies to show the equivalence of cryopreserved cells to fresh cells. The question is: who will perform the comparability studies, and when? By the way, Kite performed the comparability studies early in the development of Yescarta, and used cryopreserved leukapheresis material during their clinical trials so they were well prepared for commercialization.
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Okay Doc, we'll see.
Thanks for the clarification iwasadiver.
ski, it might be a good idea to take the time to read the published study by the Flaskworks’ technical team, and peruse their patents to inform your speculations. I’ve already replied to you in another post that in both the published study, and in the patents, the Flaskworks’ system was placed in a conventional incubator on a bench top during the maturation process to control temperature and CO2 levels. I’m not sure if this is the currently designed system though, and while I don’t ever recall reading anything about the system being stackable, perhaps it could be. However, it’s completely unnecessary and makes no sense to stack them, so most often the simplest and proven solution is the one that is used. In my opinion, the point is irrelevant, so speculate away.
Northwest Biotherapeutics has an ancillary services agreement with Advent Bioservices to oversee the construction and development of the Sawston manufacturing facility, which includes testing the Flaskworks system and developing an automated process. Milestones in the Flaskworks Purchase Agreement require that the Flaskworks’ technical team assist Advent Bioservices for the deployment and comparability studies of the Flaskworks’ system, as well as the preparation of the necessary documentation for submission to the regulatory agencies in the UK, US, Canada and EU. Nowhere in this agreement does it state that Cognate, Charles Rivers Labs, or UCLA will be conducting any validation activities with the Flaskworks’ system, and I’m not sure why so many posters on this board continue to perpetuate this notion.
You have got to be kidding, right? No offense to skitahoe, but just about everything in that post you’re replying to is wrong.
- The current manual production process is “open” which means there can not be more than one patient’s cells in a clean room at a time.
- There are not “cell lines.” This is a personalized cell therapy, so there is only a single patient’s cells.
- There are no robots!!!!!!
- DCVax-Direct has it own patented process that uses a bagged culture system, not the flask culture system used in the Flaskworks’ system. It likely requires this bagged system for the delayed maturation process.
- The Flaskworks’s system cannot be stacked.
- Elon Musk is not developing robots to service multiple Flaskworks devices!!!!! (this has to be a joke)
—————————————
Why do you think there were other companies that wanted the Flaskworks’ technology? It’s specialized to close and automate the culturing process strictly for dendritic cells, which makes it a pretty small group of companies that would even be interested. It seemed like a pretty routine acquisition according to the filing, and no mention of a bidding war.
Are you saying that you think Charles Rivers Labs is working with the Flaskworks’ equipment? And you’re guaranteeing this?
I doubt they are doing parallel equivalency runs with the Flaskworks’ system yet. The current production is in London, so these can’t be started until after Sawston is certified. You’ll notice Northwest has stated that initial practice runs and optimization of the Flaskworks system MAY begin this summer, and then a regulatory validation process will occur after sufficient practice runs have been completed. This is a major process change that will require an extensive equivalency study, which unfortunately won’t be “quick.”
I didn’t think you agreed with me senti, and it’s not about being right or wrong, but I wanted to know if you understood how everyone in the financial world does the calculation. The quarterly filing is a factual snapshot of the financial situation of the company at that particular point in time, and why I prefer to use those numbers, even if somewhat dated. As I’ve said, there’s a lot of financial activities occurring during the quarter, so you could certainly be correct about their current situation.
Agree Hbpainter, that 17 acres could be one of those rabbits, but I’m afraid that it might be stuck in the hat! Are you still keeping an eye on the rezoning permits? Seems so long ago. And yeah, I thought it was just Northwest Bio that was slow . . .
Thanks Gus, appreciate the confirmation and your insights. In the first half of the year, I think ~5 million shares were issued for debt conversions, so it’s definitely something to keep an eye on as available shares dwindle, but probably not a major issue yet. I suspect the current number available is higher than 20 million because they suspended almost 4 million additional options in July, and I assume they’ll continue to suspend more in the coming months. I think your views tend to be more pessimistic than mine, and certainly more than the eternal optimist senti’s. :)
Of course I read the terms of the recently issued four-month notes with great interest, and I think it does indicate that data release is likely to occur before November. And yes, I think it’s safe to assume that Les has been working the phones in anticipation of a private placement among the small stable of accredited investors that have continually supported the company, but guessing that it’s just to gage interest right now. I don’t agree with your characterization of these financings as “toxic,” but, I know what you’re saying. Although it’s not ideal, at this point there’s already been massive dilution, and since a placement and smaller follow-on will occur after the data release, it will be at a higher price, whatever that is. If a small group of investors, who have continued to provide funding to keep the company afloat, are able to get a favorable price, so be it.
I was thinking the private placement and folllow-on offering would catch the company up with creditors and (along with warrant exercises) provide a little breathing room until the company could hold a special shareholder meeting early next year to propose an increase in authorized shares and/or a reverse split, and then file a new shelf. I didn’t think they had to wait until next spring’s annual meeting for this as long as the Q3 filing in November is on time, but I’m not sure.
No problem senti, but now I’m curious. Can we at least agree that as of June 30, they were 25,256,000 shares under the authorized limit? (since this is a fact)
857,230 Common Stock Outstanding
312,035 Warrants Outstanding
+305,779 Stock Options Outstanding
————
1,475,044 Total Common Stock, Warrants, and Options Outstanding
- 300,300 Total Warrants and Options suspended - (241.5 million options + 58.8 million warrants)
————
1,174,744 Total Common Stock, Warrants, and Options Outstanding excluding suspended Warrants and Options
———————————————
———————————————
1,200,000 Share Authorization Limit
- 1,174,744 Total Common Stock, Warrants, and Options Outstanding excluding suspended Warrants and Options
—————
25,256 Shares Available
What we can be certain of is that the company has room to spare and shares to still use to raise funds after data release
Thank you sharpie - excellent news!
Hi senti, I double checked, and the numbers in my post below, as of June 30, were accurately transposed directly from the tables in the Q. It’s not necessary to perform any calculations, as the numbers are given under each heading. (i.e. common stock, warrants, and options) The only calculation necessary is adding them up, and then subtracting the suspended warrants and options, as I have done.
My numbers subsequent to the end of the quarter were indeed off. I didn’t notice that the 15.2 million shares of common stock issued during July and August were issued upon warrant exercises, so that probably did not affect the authorized limit. (unless some was cashless) However, the additional 3.7 million options that were suspended in July, should be added to the 25.25 million shares available, so best guess, they are currently approximately 29 million shares under the authorized limit.
hyperopia Wednesday, 08/18/21 03:48:21 PM
Re: hankmanhub post# 396222
Post # 396598 of 396735
hank, approximately 25 million shares under the authorized limit, as of June 30, or between 13-14 million shares under the cap currently, by my calculations:
Common Stock Outstanding as of June 30 - 857,230
Warrants Outstanding as of June 30 - 312,035
Stock Options Outstanding as of June 30 - 305,779
Total Common Stock, Warrants, and Options Outstanding - 1,475,044
Total Warrants and Options suspended - 300,300 (At June 30, 2021, approximately a total of 241.5 million options and 58.8 million in underlying warrants were under block or suspension agreements)
Total Common Stock, Warrants, and Options Outstanding excluding suspended Warrants and Options - 1,174,744
Share Authorization Limit - 1,200,000
Note: during July and August, just over15 million shares of common stock were issued, and almost 4 million additional options were suspended.
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I didn’t see your previous post senti, since I’m pretty far behind, but our numbers are way off. I was not the most dedicated student at the University of Hawaii, which itself is not exactly known as a bastion of higher education, so you could be right. :) But, I’ve never seen it calculated the way you did. That 1.174 figure that I got was as of June 30, from the tables in the Q, so that should be pretty close. Just glancing at your numbers, I can see your warrant figure is way different than what was listed in the table of the Q.
I generally don’t dig too deep into subsequent financing actions as they’re often on-going and changing during the current quarter. I merely glanced at the subsequent actions and notes to get the 15 million shares issued and the 4M additional warrant suspensions to calculate the 13-14M current figure, so that could certainly be off. If it was the result of warrant exercise, then that would reduce that liability.
Anyway, I don’t have time to double check right now, but I might tomorrow. I do think you’re correct about the friendlies who own many of those warrants helping Northwest Bio if they can, but I haven’t had time lately to verify the expiration dates of the warrants. Is that what Bigger’s comment the other day on Twitter was about? Was this discussed?
hank, approximately 25 million shares under the authorized limit, as of June 30, or between 13-14 million shares under the cap currently, by my calculations:
Common Stock Outstanding as of June 30 - 857,230
Warrants Outstanding as of June 30 - 312,035
Stock Options Outstanding as of June 30 - 305,779
Total Common Stock, Warrants, and Options Outstanding - 1,475,044
Total Warrants and Options suspended - 300,300 (At June 30, 2021, approximately a total of 241.5 million options and 58.8 million in underlying warrants were under block or suspension agreements)
Total Common Stock, Warrants, and Options Outstanding excluding suspended Warrants and Options - 1,174,744
Share Authorization Limit - 1,200,000
Note: during July and August, just over15 million shares of common stock were issued, and almost 4 million additional options were suspended.
Haha. Good to know.
belated thanks flipper!
Thanks for the reminder longfellow, it’s been a while since I’ve looked at that. The full question from my initial post was “We all know that the administration, source of antigen, (lysate vs. tumor tissue in vivo) activation method, and maturity of the cells are different, but what specifically in the cell characteristics and critical quality attributes of the actual dendritic cells are different?” So yes, I’m aware of many of the basic differences required for injection into a tumor’s hostile microenvironment vs. intradermal, as well as the delayed activation (method B) used in that -Direct trial. But that's a good point about the process being the product
So you think Dr. Bosch is the one to ask instead of ex?
That still didn’t answer the question of “what specifically in the cell characteristics and critical quality attributes of the actual dendritic cells are different?” but I appreciate the extra effort, and no further bumbling around is necessary. We’ve all seen behind the curtain now, and it’s pretty clear that you have no business telling Dr Bala or anyone else about “a lack of understanding of the basic science.” If Linda Powers says that the therapeutic cells of DCVax-L and DCVax-Direct are essentially “the same” based upon their experience and testing with sophisticated assays, then I believe it. I still think -Direct will have its own label, but it may have an accelerated pathway after -L is proven.
That’s what I thought ex. Your claim was that -L and -Direct are different, and I would like to know exactly what makes them different, but you go on about other companies dendritic cells, and again make the very same claim (without proof) that they are very different agents. Maybe you didn’t answer my question, but you certainly revealed a lot in your answer. Thank you for your time.
By the way, if anyone can answer this question, I would seriously like to know.
ex, since you seem to have a deep understanding of the basic science, then perhaps you can explain what exactly separates the dendritic cells of -L and -Direct. As someone who clearly doesn’t possess your superior knowledge of the basic science, I’ve wondered about that myself. We all know that the administration, source of antigen, (lysate vs. tumor tissue in vivo) activation method, and maturity of the cells are different, but what specifically in the cell characteristics and critical quality attributes of the actual dendritic cells are different?
Please feel free to use these examples and claims made in Northwest Bio’s patents for their assays:
The following examples are provided merely as illustrative of various aspects of the invention and shall not be construed to limit the invention in any way.
Examples
Example 1: Co-Stimulation Assay
In this example, an antigen-independent co-stimulation assay is used to measure the quality of preparations of dendritic cells.
Dendritic cells preparations were made from 26 different human subjects, as follows: PBMC were isolated from leukophereses blood from each patient and cultured for 6 days in OptiMEM media (Gibco-BRL) supplemented with 5% autologous plasma, followed by another day of culture in the presence of BCG, a dendritic cell maturation agent.
Peripheral blood mononuclear cells (PBMC's) were prepared as follows: Leukopheresed blood was diluted with buffered saline, overlaid upon FICOLL solution and spun for 20 minutes at 2000 rpm. The white cells at the interface were isolated. The co-stimulatory function was removed from PBMC using magnetic bead selection. Briefly, antibodies for MCH class II were coupled to magnetic beads (Dynal Corp., New York). The magnetic beads were added to PBMC to remove cells having MHC class II molecules as follows: Beads were added to PBMC at 2-10 beads per cell, and incubated for one hour. Following this incubation, bead-bound cells (APC) were removed using a magnetic device. The resulting population of PBMC were largely APC-free and contained >50% T cells.
The proliferation assay was performed as follows: 1×104 dendritic cells were added to each well of a 96-well culture plate and contacted with 1 ng of anti-CD3 antibody (BD Pharmingen, San Diego, Calif.). Then 1×105 enriched T cells (supra) were added, resulting in a final volume of 0.2 ml per well. The plate was incubated for 26 hours, and then pulsed with 3H-thymidine. The plate was further incubated for 18 hours before harvesting and determination of incorporated label.
T cell proliferation (delta cpm) was measured as the difference between 3H-thymidine incorporation by T cells stimulated with a sample of the dendritic cell preparation in the presence of anti-CD3 antibody minus 3H-thymidine incorporation by T cells stimulated with the sample of the dendritic cell preparation alone. The mean delta cpm for each dendritic cell preparation was calculated as the mean of triplicate samples.
The results of the assay are shown in the following Table 1.
TABLE 1 Co-Stimulatory Assay T Cells T Cells Plus T Cells Plus Dendritic Cell T Cell Plus Dendritic Dendritic Cells Delta Lot Number Lot Number Anti-CD3 Cells Plus Anti-CD3 CPM DCA003JY00 T031JY00 320 497 35987 35490 DCA004AU00 T031JY00 320 700 39642 38942 DCA005SE00 T031JY00 320 2813 23660 20847 DCA006NV00 T031JY00 320 812 42240 41428 DCA006SE00 T031JY00 320 355 23380 23025 DCA007SE00 T031JY00 320 8222 27384 19162 DCA008DE00 T031JY00 320 1569 49510 47941 DCA008OC00 T031JY00 320 1468 66710 65242 DCA009OC00 T031JY00 320 1058 53471 52413 DCA010NV00 T031JY00 320 3813 60498 56685 DCA011JA01 TC029JAN01 281 1432 74576 73144 DCA012AP01 TC029JAN01 405 3586 29635 26049 DCA012MA01 TC029JAN01 281 3324 49232 45908 DTX003MA01 TC029JAN01 405 665 32919 32254 DTX011JU00 T031JY00 320 274 27906 27632 DTX014AU00 T031JY00 320 302 22958 22656 DTX016SE00 T031JY00 320 774 53728 52954 DTX017NV00 T031JY00 320 484 27592 27108 DTX017OC00 T031JY00 320 632 28670 28038 DTX018OC00 T031JY00 320 1395 52347 50952 DTX020OC00 T031JY00 320 327 24655 24328 DTX021JA01 TC029JAN01 690 6916 42546 35630 DTX022JA01 TC029JAN01 690 4746 41172 36426 DTX023JA01 TC029JAN01 690 7977 51403 43426 DTX024MA01 TC029JAN01 281 1242 66374 65132 DTX025MA01 TC029JAN01 405 3932 44554 40622
T cells incubated with anti-CD3 antibody alone exhibited a mean cpm of about 370. This low level of 3H-thymidine incorporation establishes that anti-CD3 antibody was added at suboptimal concentrations. T cells co-cultured with a sample of the dendritic cell preparation alone exhibited an average cpm of about 2281 cpm. In contrast, the mean delta cpm for T cells co-cultured with anti-CD3 antibody and the dendritic cells was 39,747 cpm, with a standard deviation of 14,972 cpm. The distribution of the delta cpm values was normal, but with significant skewing to the higher end of the range of delta cpm values.
A reference sample of a dendritic cell preparation from a normal human donor had a mean delta cpm of about 51,260, with a standard deviation of 12,911 cpm. Based on these data, dendritic cell preparations exhibiting proliferation of 15,000 delta cpm or greater were found to be of acceptable quality.
Example 2: Specificity of the Antigen Independent Co-Stimulation Assay
The co-stimulation assay is based on the ability of certain types of APCs to stimulate antigen-independent T cell proliferation. The following studies were performed to establish the specificity of the assay.
The non-dendritic cell types most commonly found in dendritic cells preparations were prepared and used in the co-stimulatory assay alone and spiked into a characterized (reference) dendritic cell preparations. T cells, B cells and monocytes were purified from peripheral blood mononuclear cells (PBMC) by magnetic bead separation with negative-selection using antibodies. For T cells, antibodies to HLA-DR, CD19 and CD56 were used; for B cells, antibodies to CD2, CD3 and CD14 were used. For monocytes, antibodies to CD3, CD19 and CD56 were used.
The assays were performed as follows: T cells, B cells and monocytes were used instead of dendritic cells in the proliferation assay, as described in Example 1. T cells, used in place of dendritic cells, were irradiated to prevent proliferation. Then allogenic indicator T cells were added and proliferation determined 40 hours later, as described supra.
T and B lymphocytes, when used in place of dendritic cells, were unable to stimulate T cells in the co-stimulatory assay at any of the concentrations tested. As shown in the following Table 2, monocytes isolated from PBMC were able to stimulate T cell proliferation (3H-thymidine incorporation) when added at 2.5 times the cell number of dendritic cells. However, the proliferation was much lower than that obtained using an equal number of dendritic cells.
TABLE 2 Monocytes Dendritic Cells Number of Cells Delta CPM Number of Cells Delta CPM ?50 × 103 ~16,000 ?50 × 103 ~39,000 ?25 × 103 ~6,000 ?25 × 103 ~43,000 ?13 × 103 ~2,000 ?13 × 103 ~32,000 6.3 × 103 ~0 6.3 × 103 ~16,000 3.1 × 103 ~0 3.1 × 103 ~7,000 1.6 × 103 ~0 1.6 × 103 ~2,000 0.8 × 103 ~0 0.8 × 103 ~0 0.4 × 103 ~0 0.4 × 103 ~0
CD14 positive, CD11c positive cells and CD14 negative, CD11c positive cells in dendritic cell preparations were found to have equivalent co-stimulatory activity and were both considered to be dendritic cells.
Example 3: Characterization of Dendritic Cells
The co-stimulatory activity of CD11c positive, CD14 positive cells and CD11c positive, CD14 negative were separated from a preparation of dendritic cells by fluorescent activated cell sorting (FACS) using labeled antibody against CD14 (Pharmingen).
In these assays, CD11c positive, CD14 positive cells and CD11c positive, CD14 negative cells from the dendritic cell preparation appeared to have equivalent co-stimulatory activity. Thus, both cell types were collectively referred to as dendritic cells.
Example 4: Effect of Dendritic Cell Viability on the Co-Stimulatory Assay
The possible effect of dead cells on an assay according to the present invention was determined. Briefly, dendritic cells were killed by treatment with 1% formaldehyde for 30 minutes or by heating to 56° C. for 1 hour. These dead (killed) cell suspensions were tested in a co-stimulatory assay. The dead cells were mixed with live dendritic cells at defined ratios. The assays were performed as described above in Example 1, except as otherwise described below.
As shown in the following Tables 3 and 4, heat-killed dendritic cells retained essentially no activity in a co-stimulatory assay according to the present invention. Formaldehyde-treated dendritic cells still retain about 20% live dendritic cells, as determined by propidium iodide staining; these cells retain co-stimulatory activity at reduced levels. In a third experiment, the addition of killed cells did not interfere with the assay.
TABLE 3 Effect of Cell Viability on Co-Stimulatory Assay Cells Used Per Well Viability Delta cpm 104 live DC 100% 27482 104 total DC 63% 15791 104 formaldehyde-fixed DC 20% 6957 104 heat-killed DC 4% -42
TABLE 4 Effect of Dead Cells on Co-Stimulatory Assay Number or Dead Cells Kill Delta Added per Well Method cpm 1000 Formaldehyde 27,076 2000 Formaldehyde 27,336 3000 Formaldehyde 27,661 5000 Formaldehyde 26,478 1000 Heat 25,391 2000 Heat 24,270 3000 Heat 23,560
Example 5: Linearity of the Antigen-Independent Co-Stimulation Assay
Increasing numbers of dendritic cells were added to fixed numbers of indicator T cells to determine the relationship between dendritic cell number and 3H-thymidine assay. Zero, 2000, 6000 or 10,000 dendritic cells were placed in wells. The following culture conditions were used, as described in Example 1 (e.g., 1 ng of anti-CD3 antibody per well with 105 T cells). The total incubation time was 40 hours; the last 18 hours of incubation was performed in the presence of 3H-thymidine.
3H-thymidine uptake of indicator T cells increased substantially linearly as the number of dendritic cells increased In particular, the delta cpms observed were 0, about 7,000 cpm, about 15,000 cpm and about 27,000 cpm, respectively. The formula y=2.7183-134.13 (R2=0.9879) approximated this linear relationship. These results demonstrated that co-stimulatory activity can be linearly dependent on the number of DC.
Example 6: Precision
The precision of a co-stimulation assay according to Example 1 was determined by having three operators test the same lot of dendritic cells. Each operator tested the lot three times, once a day on three consecutive days. The data were analyzed for duplicability (intra-assay variance), repeatability (inter-assay variance), and reproducibility (inter-operator variance). The raw data are shown in the following Table 5. The coefficient of variation (CV) ranged from 1.25 to 16.18, with higher CV observed at lower levels of 3H-thymidine incorporation.
TABLE 5 Precision Of The Co-Stimulation Assay - Raw Data Indicator T Cells With Dendritic Cells With Antigen Without Anti-CD3 Antibody CPM CPM CPM Mean SD CV Oper- Day 1 856 947 940 914 50.6 5.54 ator 1 Day 2 3161 3769 3190 3373 343.0 10.17 Day 3 1126 1113 1226 1155 61.8 5.35 Oper- Day 1 870 1180 946 999 161.6 16.18 ator 2 Day 2 1092 1297 1379 1256 147.8 11.77 Day 3 3853 4249 4599 4234 373.2 8.82 Oper- Day 1 977 1223 1132 1111 124.4 11.20 ator 3 Day 2 913 1011 1218 1047 155.7 14.87 Day 3 1556 1835 2118 1836 281.0 15.30 Indicator T Cells With Dendritic Cells With Antigen Without Anti-CD3 Antibody % CPM CPM CPM Mean SD CV Oper- Day 1 24248 23523 26526 24765.67 1567.00 6.33 ator 1 Day 2 69711 73655 64396 69254 4646.39 6.71 Day 3 29232 31084 30453 30256.33 941.53 3.11 Oper- Day 1 26383 25821 26390 26198 326.51 1.25 ator 2 Day 2 35386 34414 31738 33846 1889.16 5.58 Day 3 36821 35714 38678 37071 1497.73 4.04 Oper- Day 1 31390 31968 32644 32000.67 627.64 1.96 ator 3 Day 2 28011 31085 28443 29179.67 1664.14 5.70 Day 3 42181 40188 44625 42331.33 2222.32 5.25
All conditions were run in triplicate, so triplicate cpm values were examined as a measure of duplicabilty. Repeatability and reproducibility were analyzed using delta cpm. The mean delta cpm, standard deviation and inter-assay Coefficient of Variation (CV) for each operator are depicted in the following Table 6. The CV of Operator #1 was 57.8%, for Operator, 2 14.4%, and for Operator 3, 19.6%. Reproducibility is represented by the CV of the mean delta cpm for all three operators and is 14%.
TABLE 6 Repeatability And Reproducibility Mean Coeffi- Delta Delta Delta Delta Standard cient of cpm cpm cpm cpm Deviation Variation Operator 1 23852 65881 29101 39611 2901 57.8 Operator 2 25199 32590 32837 30209 4340 14.4 Operator 3 30890 28133 40495 33173 6489 19.6 MEAN 34331 4807 14.0
Example 6
PSMA-loaded dendritic cells are assayed as follows: The loaded dendritic cells are lysed using a detergent, and the lysate equivalent of 5×105 cells is electrophoresed in each lane of a 7.5 percent SDS PAGE gel. After resolution of the lysate proteins at 150 volts for about an hour, the proteins are transferred to a PVDF or nylon membrane. Western blotting is performed using a PSMA-specific monoclonal antibody, 4D8 (ATCC HB 12487; U.S. Pat. No. 6,150,508). The binding of antibody is visualized by chemiluminescence and exposure to film. The identity of PSMA is determined by co-localization of a standard PSMA protein run on the gel.
The previous examples are provided to illustrate, but not to limit, the scope of the claimed inventions. Other variants of the inventions will be readily apparent to those of ordinary skill in the art and encompassed by the appended claims. All publications, patents, patent applications and other references cited herein are hereby incorporated by reference.
Claims
1. A method for determining the quality of the antigen-independent, co-stimulatory activity of a population of antigen presenting cells (APCs), comprising:
providing allogeneic T cells having a known functional activity and being substantially free of co-stimulatory activity;
providing a sample of APCs of unknown co-stimulatory activity;
contacting the T cells with a sub-optimal concentration of an antigen-mimetic agent, wherein the antigen-mimetic consists of a CD3 binding agent that is an antibody, a plant lectin, or a mitogen;
contacting the T cells with the sample of APCs of unknown co-stimulatory activity;
determining the activation of the T cells contacted with the antigen-mimetic agent and the sample of APCs; and
comparing the determined activation of the T cells with a standard activation index for the T cells to determine the quality of the co-stimulatory activity of the population of APCs.
2. The method of claim 1, wherein the T cells and the APCs are syngeneic, or allogeneic.
3. (canceled)
4. The method of claim 1, wherein the CD3 binding agent is anti-CD3 antibody, or an antigen binding fragment thereof.
5. The method of claim 1, wherein the APCs are dendritic cells.
6. The method of claim 5, wherein the dendritic cells are mature dendritic cells derived from immature dendritic cells by contacting ex vivo with a dendritic cell maturation agent, or the dendritic cells are immature dendritic cells.
7. (canceled)
8. The method of claim 1, wherein the T cells have been substantially depleted of peripheral blood mononuclear cells expressing CD14, CD54, CD80, CD83 or CD86 molecules on their cell surface, or the T cells have been substantially depleted of peripheral blood mononuclear cells expressing MHC class II molecules on their cell surface.
9. (canceled)
10. The method of claim 1, wherein the activation of the T cells is determined by 3H-thymidine uptake assay, by assaying T cell cytokine production, or is determined by detecting the modulation of expression of a T cell activation marker.
11. (canceled)
12. The method of claim 10, wherein the assayed T cell cytokine production is IFN? or Interleukin 2 production, the assayed T cell cytokine production is extracellular cytokine production, or the assayed T cell cytokine production is intracellular cytokine production.
13-15. (canceled)
16. The method of claim 10, wherein the T cell activation marker is CD25, CD69, CD44 or CD125.
17. The method of claim 16, wherein the T cell activation marker is detected using labeled antibody capable of binding to the T cell activation marker.
18. The method of claim 1, wherein comparing the determined activation with the standard activation index includes comparing the determined T cell activation with activation of the T cells contacted with the sample of dendritic cells alone to determine the quality of the dendritic cells.
19. The method of claim 1, wherein the standard activation index is a threshold value, or is a range of values, each value associated with a predetermined quality of dendritic cells.
20. (canceled)
21. The method of claim 1, further comprising determining presentation of a predetermined antigen by the APCs.
22. The method of claim 21, wherein presentation of the predetermined antigen is determined by Western blotting, flow cytometry or activation of antigen-specific T cells.
23. A method for determining the quality of the antigen-independent co-stimulatory activity of a preparation of dendritic cells, comprising:
contacting a first quantity of T cells, which are substantially free of co-stimulatory activity and have a known functional activity, with a suboptimal quantity of an antigen-mimetic agent, wherein the antigen-mimetic consists of a CD3 binding agent that is an anti-CD3 antibody, a plant lectin, or a mitogen, and with a first sample of a dendritic cell preparation of unknown co-stimulatory activity;
determining a first activation value for the first quantity of T cells;
contacting a second quantity of T cells with a second sample of the dendritic cell preparation or the suboptimal quantity of the antigen-mimetic agent;
determining a second activation value for the second quantity of T cells; and
comparing the first and second activation values to determine the quality of the co-stimulatory activity of the dendritic cell preparation.
24. The method of claim 23, wherein the T cells are allogeneic with respect to the dendritic cell preparation, or wherein the T cells are syngeneic with respect to the dendritic cell preparation.
25. (canceled)
26. The method of claim 23, further comprising determining presentation of a predetermined antigen by the dendritic cells.
27. The method of claim 26, wherein presentation of the predetermined antigen is determined by Western blotting, flow cytometry or activation of antigen-specific T cells.
28. A method for determining the quality of a preparation of dendritic cells, comprising:
(1) providing a dendritic cell preparation of unknown co-stimulatory activity and unknown antigen presenting ability for a predetermined antigen;
(2) determining the co-stimulatory activity of the dendritic cell preparation, said determination of co-stimulatory activity comprising (a) providing allogeneic T cells of known functional activity and substantially free of co-stimulatory activity; (b) contacting the T cells with a suboptimal quantity of an antigen-mimetic agent, wherein the antigen-mimetic is a CD3 binding agent consisting of an anti-CD3 antibody, or an antigen binding fragment thereof, a plant lectin, or a mitogen, and with a first sample of the dendritic cell preparation; (c) determining the activation of the contacted allogeneic T cells; and (d) comparing the determined activity of the contacted T cells with the standard activation index for the T cells to the determined co-stimulatory activity of the dendritic cell preparation;
(3) determining presentation of the predetermined antigen by the preparation of dendritic cells, said determination of presentation comprising: (a) contacting a second sample of the dendritic cell preparation with the predetermined antigen; and (b) determining the amount of predetermined antigen presented by the dendritic cells; and
(4) determining the quality of the dendritic cell preparation based on the determined co-stimulatory activity and determined antigen-specific presentation of the predetermined antigen.
29. The method of claim 28, wherein the antigen-mimetic agent is a CD3 binding agent, a plant lectin or a mitogen.
30. The method of claim 28, wherein the dendritic cells are mature dendritic cells derived from immature dendritic cells by contacting ex vivo with a maturation agent, wherein the dendritic cells are immature dendritic cells, or wherein the T cells have been substantially depleted of peripheral blood mononuclear cells expressing MHC Class II, CD14, CD54, CD80, CD83 or CD86 molecules on their cell surface.
31-32. (canceled)
33. The method of claim 28, wherein the activation of the T cells is determined by 3H-thymidine proliferation assay, by assaying T cell cytokine production, or by expression of at least one T cell activation marker.
34. The method of claim 28, wherein the activation of the T cells is determined by assaying T cell cytokine production.
35. The method of claim 34, wherein the T cell cytokine production is IFN? or Interleukin 2 production, wherein the T cell cytokine production is extracellular cytokine production, or wherein the T cell cytokine production is intracellular cytokine production.
36-38. (canceled)
39. The method of claim 33, wherein the T cell activation marker is CD25, CD69, CD44 or CD125.
40. The method of claim 39, wherein the T cell activation marker is detected using labeled antibody capable of binding to the T cell activation marker.
41. The method of claim 28, wherein determining the co-stimulatory activity includes comparison of the determined T cell activation with a standard activation index for the T cells.
42. The method of claim 41, wherein the standard activation index is a threshold value, or is range of values, the values associated with different predetermined co-stimulatory activities.
43. (canceled)
44. The method of claim 28, wherein presentation of the predetermined antigen is determined by Western blotting, flow cytometry or activation of antigen-specific T cells.
Right Doc, optimally activated DC’s are injected at the periphery of the tumor where they are exposed to the dead and dying tumor cell’s antigens. And yes, as jondoeuk likes to note, the tumor microenvironment is very difficult for immunotherapies to overcome, which is why “method B” is so critical. As the Phase I proved, delayed activation circumvents the tumor’s defenses.
And speaking of “method B, ” I’m reminded why the Flaskworks’ equipment likely won’t be used to produce DCVax-Direct. This delayed activation isn’t possible with the flask culture system and may be the reason why DCVax-Direct uses a bagged culture process.
DCVax®- DIRECT: autologous activated dendritic cells for image guided intra-tumoral vaccination in patients with solid tumors - a phase I/II clinical trial in progress
Dendritic cells (DC) are acknowledged to be quintessential in the armamentarium to mount anti-tumor immune responses and have been utilized in varying capacities for cancer immunotherapy. Recent advancements & lessons leant from prior DC therapies have revealed that major barriers hinder the efficacy of cancer vaccination with DC, principal of which is the hostile environment of the local tumor milieu that inhibits activation and subsequent maturation of DC. This critical step is required to process and present antigens (tumor cell) to the downstream cascade of immune mediators. The therapeutic goals of cancer vaccination are the induction of tumor regression secondary to the production of tumor specific immune factors and local inflammatory cytokines with enhancement of long term anti-tumor surveillance to prevent recurrences. DCVax®- Direct (Northwest Biotherapeutics, Inc. Bethesda, MD) are autologous dendritic cells activated Ex vivo with BCG and IFN? for intratumoral injection and attempts to circumvent this barrier thereby maximize the induction of anti-tumor responses. Autologous DC will be harvested from peripheral blood monocytes via leukapheresis. Following Ex vivo DC maturation, inoculation of the tumors will be performed 2 weeks later utilizing image guidance to ensure activated DC deposition at the peripheral aspect of the tumor thereby enhancing DC exposure to antigens from dead or dying tumor cells. Vaccination will be performed at least every week for 3 weeks, and subsequently at longer intervals dependent on harvested DC availability. Phase I/II study with DCVax®- Direct will enable evaluation of the safety, MTD, and responses in patients with solid tumors. The secondary objective addresses the feasibility, anti-tumor immune responses, PFS and OS. At the time of this poster submission, the 'First-in-man' patient has been consented for the study. We propose to present our initial findings at the SITC 2013 conference as more data will be available.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991184/
Okay, now I’m kinda regretting that I even pointed that out, but that “wordsmith” section from the 10-K bothered me when I originally read it, and then you inadvertently brought it up in this post that I replied to. (which was an excellent rebuttal to ex by the way)
As for disclosing the analysis plan in their top line PR... are you joking? Remember, they've indicated it was phone book sized... how on earth could they disclose the SAP in their PR? They've already disclosed the endpoints in the last Q
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=164974255
Did Northwest Bio actually disclose the endpoints? Where does it say what the new endpoints are?
This was under the risk factors in the 10-K:
Quote:
We may not receive regulatory approvals for our product candidates or there may be a delay in obtaining such approvals.
Our products and our ongoing development activities are subject to regulation by regulatory authorities in the countries in which we and our collaborators and distributors wish to test, manufacture or market our products. For instance, the FDA will regulate our product in the U.S. and equivalent authorities, such as the MHRA and EMA will regulate in Europe and other jurisdictions. Regulatory approval by these authorities will be subject to the evaluation of data relating to the quality, efficacy and safety of the product for its proposed use, and there can be no assurance that the regulatory authorities will find our data sufficient to support product approval of DCVax-L or DCVax-Direct. In addition, the endpoint against which the data is measured must be acceptable to the regulatory authorities, and the statistical analysis plan for how the data will be evaluated must also be acceptable to the regulatory authorities. The statistical analysis plan that we submitted to regulators for the Phase III trial embodies a different primary endpoint and secondary endpoint than did the original Protocol for the trial. Under the Protocol the primary endpoint was progression free survival, or PFS, and the secondary endpoint was overall survival, or OS. Both of these endpoints were confounded: the PFS endpoint by pseudo-progression, and the OS endpoint by the “crossover” provision in the trial design, which allowed all of the patients in the trial to cross over to DCVax-L treatment after tumor recurrence (while remaining blinded as to which treatment they received before tumor recurrence). The statistical analysis plan uses external control patients rather than within-study controls. There can be no assurance that regulatory authorities will allow a product approval to be based upon this approach.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=164976734
I doubt anybody in science would ever consider -L results to apply to Direct just because they share a similar name. Very unrelated.
Why did "Method B" vanish when they had later results?
Ha ha. I’m not sure who else is on the list, but you will definitely be invited to the NWBO celebration party! Somehow, I don't think it would be the same without you.
Perhaps it’s headlines like these for example? Pretty easy to find similar headlines for Merck’s Keytruda.
Bristol Myers Seeks Redeeming Combination for Struggling Checkpoint Inhibitor
Published: Jul 27, 2021 By Vanessa Doctor, RN
https://www.biospace.com/article/bridgebio-bristol-myers-squibb-start-clinical-trial-to-treat-advanced-solid-tumors-with-kras-mutations/
Bristol Myers pulls lymphoma indication for Istodax after confirmatory trial falls flat
August 2, 2021 05:05 PM EDT Kyle Blankenship
https://endpts.com/bristol-myers-pulls-lymphoma-indication-for-istodax-after-confirmatory-trial-falls-flat/
Both of these BP’s have or had combo trials with DCVax set up, so they certainly know of Northwest Bio . . . . but then you probably knew that.
Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen Vaccine and Nivolumab in Treating Patients With Recurrent Glioblastoma
https://clinicaltrials.gov/ct2/show/NCT03014804?term=NCT03014804
Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma
https://clinicaltrials.gov/ct2/show/NCT04201873?term=NCT04201873
And Merck exec’s have said that they are particularly interested in immunotherapies which show efficacy as a monotherapy . . . .
Drugmakers struggle to find immunotherapy combinations for cancer
David Crow in New York MAY 30, 2018
Roger Perlmutter, Merck’s top scientist, said the company would focus its future efforts on combinations where each of the drugs has been proven to work separately as a “monotherapy” before testing them together. “I’d prefer to combine mechanisms where both parts of the combination have activity by themselves,” he said.
https://www.ft.com/content/d39afa5e-6066-11e8-9334-2218e7146b04
My thought was that when Sawston is certified and Advent initially begins production for compassionate use there, they will be using the same expensive, manual process by highly-skilled technicians that was transferred from the CCGTT, so the existing contract would apply. But obviously Advent's operating costs will be different, so that makes more sense.
If it’s so clear, then why do you have it so wrong? Northwest Bio has not shut down any programs nor has it made any payments for it.
Cognate was contracted to manufacture for the clinical trials, so understandably, the focus in the SEC filings was on them. The current focus is on preparations for commercial production at Sawston, and Advent has been contracted to perform that task, so the focus in the SEC documents is on them. I believe that Northwest Bio will use both contract manufacturers for commercial production, but is waiting to sign commercial manufacturing contracts until the comparability studies on the Flaskworks’ equipment has produced actionable results.
I think Advent will manufacture for the UK & EU from Sawston since it will have plenty of capacity for both markets for the next few years at least, and the lowest operating costs. Beyond that, I agree it’s fluid, and there’s a distinct possibility that Charles Rivers Labs could acquire Advent Bioservices at some point.
Thanks ATLnsider, yes I think that’s the simple explanation.
Sorry I missed that discussion. I do think they will use Charles Rivers Labs for manufacturing in the US, so it could be posturing for those negotiations, but the key factor may be the Flaskworks’ equipment.
I thought it was clear that I was making an observation and speculating, but thanks for clarifying if that was not clear.
I would think that Cognate would have run the equivalency studies for cryopreserved leukapheresis material during the trial, but keeping that language in the annual reports long after the trial was completed made me think otherwise. It’s encouraging that Northwest Bio finally addressed the need for automated manufacturing with the Flaskworks’ purchase (NEARLY A YEAR AGO) but the speed with which they operate is frustrating, and this does make me wonder if their limited resources have prevented them from addressing other manufacturing issues in a timely manner. I’m quite confident that they will eventually receive regulatory approval and begin commercial manufacturing, but I’ve begun to think it may be later rather than sooner.
BTW - Do you (or anyone else) have an explanation for the language change from this:
2019 10-K
Our intention is for the U.K. facility to manufacture DCVax products for the whole European region.
2020 10-K
Our intention is for the U.K. facility to manufacture DCVax products for both the UK and other regions.