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Hi Lykiri
What, you mean that BMY only randomised 19% of the 3034 that they enrolled in Checkmate 498?!
Shocking....
Why weren't we told??
NWBO did better than that at 21% randomised.
Funny how NWBO attracted criticism on this score, but I've never heard AVII or anyone criticise BMY for randomising an even smaller percentage of screened patients.
Mind you, it didn't do anything for their results...
Lol.
"BTW, it is Advent that actually sells Specials. So they pay NWBO a share and that is the reported revenue."
How so?
Advent is a CMO. It doesn't employ either salespeople or patient liaison folk.
The suitably-qualified UK physician who wishes to make a patient referral for treatment under the Specials scheme would make the referral to NWBO.
Who do have a patient liaison person.
Neither of us have seen the details of the contractual service agreement between NWBO and Advent. But I imagine the gross fee goes to NWBO, from which they make appropriate payment to subsidiary service providers, including Advent and the UK NHS.
Not the other way round.
Hi meirluc.
Allow me to respond.
The statement in JTM was probably more or less accurate at the time it was written: at least several months before it was published. Maybe getting on for a year..
Remember they had all the shenanigans with the "top journal" (or journals) faffing about asking for amendments and rewrites (at least that's my supposition), before they decided to pay and get it put out in a timely fashion by JTM.
By the time they got to the SNO update, they wouldn't and didn't repeat the statement (as far as I'm aware). Because by then, they would have known it was no longer accurate.
As to why, the superior survival of late entrants occurred, I like 3(a) the most.The other factors you mention may have played their part, but 3(a) was probably the most significant, in my opinion.
Regards.
Thankyou.
Am I the only one wondering why that date is in the future?
Hi HB
First time I heard Nivolumab called Ebola map!
I love those YT transcripts.
I didn't know that, Bio.
Does he work for Rentakol now then?
Hey Mav; give it the extra day.
You wouldn't want to be April fooled..
Just popped in for old times sake!
(It really is about time something happened...)
He will be the author of the critique of the journal piece, like he was last time!
Well yes, in terms of literal meaning; Advent is a UK firm.
And yes they are NWBO's contractor.
Between the lines, you could intuit a bit of further implicit meaning; that Advent first and foremost serves NWBO. Any work they take on must be consented to by NWBO, and NWBO will always have first call on facility resources and capacity allocation.
And the UK location suggests to me that NWBO's likely focus for ongoing operations is going to be the UK first, Europe second, and the US and Canada after that.
Which is fine by me, as it appears to be the rational way to go.
In the short-term, I imagine patients will be from or come to the UK, thus limiting any long-distance supply logistics, with their associated costs and regulatory complexities.
Cognate is no more; I really don't know if they are still paying to retain any reserved capacity at Memphis. If they are, I would be wondering what for....
They can't really focus on all fronts at the same time with their limited resourcing, and their apparent current primary focus on the UK does seem a logical one.
Even if one is not a total fan of every single aspect of LP's stewardship, you really have to hand it to her; the way she has got NWBO to their current position of now being poised to move forward (hopefully) to active commercial operation.
OK, so we have to get a certain P3 properly concluded first, but I can now envisage the first Direct P2 being entirely run in the UK.
Maybe a start this time next year?
And the Car-T's didn't bother with a P3, before approval was acquired.
I guess it is just a technical requirement that the registered licence holder has to have a physical presence on the site. Thus it's Advent. Don't see it as problematic in any way. And I believe that there also has to be a nominated qualified person, who will also be an Advent bod.
It is now a much more valuable resource; a licence, an onsite manufacturing team, available capacity, and potential to greatly expand that capacity (given time), either for DCVax or for other contract work.
NWBO should have referred to it as a 'licence' and not a 'license', seeing as it is in the UK!
But we won't make too much of a big deal about that..
About time this happened.
They make it sound great.
But trust me; it's not all its cracked up to be.
Lol.
kabunushi; I could respond with reams of hard and fast evidence that refutes just about everything that you assert here. And I'd be more than happy to have such a debate. But the risk of such a response going LTFU makes it probably not worth the effort.
Facts are indisputable. Assertions of facts are open to dispute.
I'll admit to being a bit of an occasional pedant on spelling. But in this instance, the spelling mistake was part of a wider inaccuracy that suggests a lack of awareness on an important issue.
An issue that is often contentious and charged. As such, wherever one stands on it, accuracy is important.
I have no problem being corrected, if I assert something that is inaccurate.
I also recognise that you bring a lot of well-informed contributions to the Board.
Current stats from an independent site that monitors VAERS:-
https://openvaers.com/covid-data
And the Harvard study from a decade ago that looked at the scale of under-reporting to VAERS:-
https://digital.ahrq.gov/sites/default/files/docs/publication/r18hs017045-lazarus-final-report-2011.pdf
Regarding your last sentence, I will simply avow that that will not be the case in this instance.
I have to say I'm shocked at the lack of awareness on this issue.
Well, not that it really matters, because we all know what we are talking about!
But it niggles a little with me after a while. Bit like Swanston or Avistan!
But in the UK, it is consistently referred to as getting licensed.
Or being granted a manufacturing licence.
Even with that, there is a cross the pond spelling issue.
We have a driver's licence (two 'c's). I think you have a driver's license...
So in the UK, licence for the noun. But licensed premises.
From the horses mouth:-
https://www.gov.uk/government/publications/human-and-veterinary-medicines-register-of-licensed-manufacturing-sites
And from that link, here is the current list. Which we are not on.
Yet!!
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1022985/MS_Register_-_October_2021.csv/preview
I think NWBO just made the same inaccuracy. Probably pandering to your side of the pond.
Y'all have a nice day!
Don't know if you have cited this reference previously, Lykiri: but we did get a brief mention in the most recent annual Catapult review of UK ATMP/GMP manufacturing, which was issued in Nov '20.
Under the 'Future Capacity and Expansion' section, it was stated:-
"Advent Bioservices is currently managing the development of a state-of-the-art facility for multiproduct GMP production outside Sawston in Cambridgeshire, which will allow scale up of commercial production and initiate the provision of contract manufacturing services. The facility consists of GMP lab space and process development and additional areas for future expansion.
Initial construction work has focused on the building of 2 separate GMP suites with grade B/C classified areas, in house QC testing and office space as well as a multipurpose cryogenic storage unit. The facility will operate the facility under a comprehensive IT infrastructure including eQMS and an eBMR, with a LIMS with secure storage for client documents and paperless systems."
Page 18.
https://ct.catapult.org.uk/sites/default/files/publication/ManufacturingReport2020_PUBLISHED.pdf
I see a lot of references (not by yourself) on IHub to Sawston getting certified (for manufacturing) shortly..
More correctly, the term is licensed.
And I hope and expect that indeed it will be licensed for manufacturing shortly!
Regards.
Have a look at this, hyperopia.
https://clincancerres.aacrjournals.org/content/clincanres/24/16/3845.full.pdf
It's probably the best available description of Direct methodology.
There are many differences between the production of Direct and the production of L and how each is administered. Differences include (but aren't limited to) degree of DC maturation, the differences in the constituents of the maturational cocktail and at what point in the process these agents are employed, site of injection, and site of antigen presentation. And a lot of the processes are proprietary anyway.
I certainly don't profess to have anything other than a very rudimentary understanding of the critical processes that are involved, and how precisely these processes differ between the two products.
Dr Bosch is probably the only individual that could give an in-depth description of the differences and similarities, and which distinctions are considered critical to the optimal efficacy of each.
We know that for Direct, Method B was considered a critical enhancement, using a different time frame to optimize the required partial DC maturation.
So, they are similar in terms of broad principles and mechanism of action, but considerably different in terms of precise detailed preparation and administration. And you could say that makes for very different products. The process is the product!
I'm sure they learned a lot from the PI, which they will employ in the P2's. Method B obviously, but other refinements including ensuring they isolate the highest functional DC precursors to start with. Plus, as we know, the injection of multiple tumors where indicated.
Even if it did (which is not at all clear), it would only be by about 5%.
Probably about the same as a one year rise in GBM incidence.
Oh, he's popped up a few times over the years, always being critical of autologous DC vaccines. He runs a lab working on a different approach, namely adoptive cell transfer (ACT) targeting specific tumor mutations.
I'm sure others can recall his prior disparaging criticisms.
Immunotherapy is a field with much professional competition. And most researchers like to think that their investigational therapy is the one with the magic bullet, so are prone to making negative comparisons about others.
Yes. That makes sense.
If a tumor shrinks, and shrinks a lot , then yes, of course I would expect it to correlate better with OS than a tumor that shrinks by a little bit. Unless special circumstances apply, such as primary tumor shrinkage happening at the same time as a metastatic process is happening.
But what is more important than depth of response is duration of response. Which that study does not look at.
And a durable response (measures by tumor shrinkage) that persists over an extended period of time, would be a better predictor than DpR.
It was more of a rhetorical question than one born out of ignorance!
Of course I know why it is employed.
There are reasons why response rate is also employed in late-stage trials; it saves a good few years. And a ton of money!
Particularly handy if you seek to get an approval from a single-arm trial.
And it's a subjective assessment. There has even been studies on how two different assessors come up with significantly different tumor measurements from the same patient.
Those reasons for its use do not make for sound assessments of true efficacy.
It's nothing more than a very imperfect surrogate. More imperfect than PFS. It is not a good predictor of overall survival.
As such, it's a pet hate of mine.
But if regulators are going to accept it, of course the industry will use it!
Prasad puts it clearly:-
"The FDA has used surrogate end points approximately 194 times to approve cancer drugs since 1992, and about 1 in 3 times, a surrogate was used for the first time in a particular type of cancer. When this is the case, the strength of association between the surrogate end point and OS is often absent or weak. This means that the FDA’s use of these surrogate measures is justified neither by strength of association (ie, ability to predict gains in OS) nor previous first use, since 1 in 3 approvals constitute the use of a surrogate end point for the first time in the treament of a specific cancer type. Our study is limited by some missing FDA label updates before 2006 that are not publicly accessible.
Surrogate end points can expedite trial completion compared with OS,4 but they add substantial uncertainty regarding whether the drugs involved improve quantity or quality of life.6 Moreover, the FDA rarely demands stringent confirmation of clinical benefit following market approval.3 We find that the FDA is steadily accepting more surrogate measures over time, which are not justified by scientific validity or adherence to regulatory precedent. This reflects a greater tolerance of risk, and if postmarketing studies are slow, incomplete, or demonstrate negative results, then patients experience harm and cost without the intended benefit."
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2764287
If one holds a purely investing standpoint, then an approval based on RR might be perfectly acceptable.
But as far as proper evidence-based medicine goes, it's not good.
Can you tell me what an ORR has got to do with living longer or living better?
"The efficacy of anti-CTLA-4, anti-PD-1, anti-PD-L1 and TIL is due to neoantigen reactive T-cells."
Do you mean the very limited efficacy?!
"Roche, BioNTech post 'low' response rate in cancer vaccine trial"
"A phase 1b trial of a personalized cancer vaccine in development at Roche and BioNTech has chalked up a “low” response rate. Nine of the 108 evaluable solid tumor patients responded when given the vaccine in combination with Tecentriq, although researchers pointed to immune response results to support continued study in other populations.
Roche’s Genentech paid BioNTech $310 million in upfront and near-term milestones in 2016 to gain access to mRNA-based personalized cancer vaccines. The collaboration gave rise to RO7198457, a drug that targets up to 20 tumor-associated antigens (TAAs) expressed by a patient’s cancer. By giving patients mRNA corresponding to TAAs, Roche and BioNTech hope to rally cytotoxic T-lymphocyte and memory T-cell-dependent immune responses against tumors.
Researchers are using this week’s virtual American Association for Cancer Research event to share an early look at whether RO7198457, also known as BNT122, works as hoped. The results contain plenty of ammunition for anyone who is skeptical about the likelihood of Roche and BioNTech ending the long losing streak of cancer vaccines.
Evaluations of 108 patients who received RO7198457 and checkpoint inhibitor Tecentriq identified nine responses, including one complete response. The figures translate into a response rate of 8%. It is unclear whether those subjects would have responded to Tecentriq given as a monotherapy. A smaller assessment of RO7198457 as a monotherapy linked the cancer vaccine to a 4% response rate.
Juanita Lopez, Ph.D., consultant medical oncologist at The Royal Marsden and co-author of the RO7198457 abstract, said the “clinical response rate overall was low” in a statement about the trial. Despite that, Lopez sees positives in the results, noting that “we were able to generate tumor-specific immune responses in the majority of evaluable patients.”
An analysis of peripheral blood taken from 49 patients found evidence of neoantigen-specific T cell responses in 77% of samples. Viewed alongside the efficacy data, the analysis suggests RO7198457 reliably elicits specific immune responses that rarely translate into reductions in tumor size.
Lopez thinks the health status of participants at baseline may explain why immune activity is failing to translate into partial and complete responses. Participants in the combination trial had received a median of three prior therapies. Almost 40% of subjects had previously received immunotherapy. It is unclear if any of the nine patients who responded to the combination had previously received an immunotherapy.
The debate over whether RO7198457 is a dud or a good drug given to the wrong patients will remain inconclusive until data from other populations are available. Roche and BioNTech began gathering such data last year by initiating a phase 2 trial of RO7198457 in combination with Merck’s Keytruda. The trial is randomizing previously untreated advanced melanoma patients to receive Keytruda as a single agent or in combination with RO7198457."
https://www.fiercebiotech.com/biotech/roche-biontech-post-low-response-rate-cancer-vaccine-trial
Yep, it's a dud.
And it's an mRNA vaccine....
I wouldn't chance my arm on this one, personally speaking.
"Aren't you aware of this?"
I am now.
As soon as I see an ICI linked with a neo-antigen vaccine, I'm afraid I lose interest, and consign it to the scrapheap of approaches destined to be unsuccessful.
What did you make of it?
You should know by now that, in my view, it is the dually autologous nature of DCVax-L that sets it apart, and is critical to its effectiveness and absence of toxicity.
No, I wasn't aware of it.
Had a look.
Didn't spot anything of particular interest.
Does it hold any particular significance for you?
If so, what is it?
It's Rosenberg.
What do you expect?
Dr Ashkan is a co-author on this just published comprehensive study in 'Neuro-Oncology', on the increasing incidence of primary brain tumours in England (not all of UK). It is the most up-to-date study of its kind (at least for England).
'Neuro-Oncology' is the official journal of SNO.
"The age-standardized incidence for glioblastoma increased from 3.27 per 100 000 population per year in 1995 to 7.34 in men in 2013 and from 2.00 to 4.45 in women."
The article gives a full breakdown of brain tumour types, and is an interesting read for GBM background information.
They conclude:-
"Results show an overall rise in the incidence rate of these tumors being diagnosed in England between 1995 and 2017. While the incidence varied for the different brain tumor subtypes, the most common brain tumors—glioblastoma and meningioma—seem to be driving this overall increase. Explanations for the increase in the number of primary brain tumors are likely to include aging of the population, improvements in access to neurosurgical care and diagnostic tools, and more complete and detailed records, including benign tumors, reaching NCRAS as a result of the regular updates in the coding of the WHO classification for CNS tumors. All these factors are likely to play a role in contributing to the incidence of brain tumors, particularly for glioblastomas and meningiomas."
I reckon they could have given consideration to other factors such ionising / EMF radiation, but that would have required a different type of technical analysis.
Seems a bit callous to think in terms of GBM 'market size'.
But suffice to say, it sure isn't shrinking.
https://academic.oup.com/neuro-oncology/article/23/8/1371/6218679
Hi hyperopia.
Thanks for the reminder on the adjuvant trial.
I have to say that that one stopped recruiting about six years ago.
And I think we had any results that we are likely to get some considerable time back. It's those 23 patients again...
The question about how important is the addition of Poly-ICLC or Imiquimod adjuvants is not really answered for me, though they may augment a treatment response.
Anyway the P3 did without.
But they could conceivably be used anyway off-label on an individual level, as both already have an approval.
I'm not so sure that they do have a pretty good idea as to who responds best to L, other than the already very apparent meth/unmeth difference. How could they? Or they might have some idea, but simply not have had the opportunity to test. For example; L without TMZ for unmeth might work better and would prevent the TMZ-induced mutational shift.
My hypothesis which is really based on nothing tangible, is that some of the UCLA guys are caught up in the 'combo is best' mantra.
Apart from anything else, such a combo would be putting the price tag up to close on $0.5M...
And surely we are not sufficiently taking into account the consistent failure to date of ICI's in brain cancer, and the HPD, auto-immune dysfunction and adaptive resistance associated with ICIs in other cancers!
My supposition is that Rob Prins is the primary enthusiast for the combo with an ICI.
Before anyone shoots me down, this is just a personal current hypothesis.
If future info or data sheds more light, and proves me wide of the mark, I'll amend my hypothesis accordingly!
"The mouse studies were certainly compelling."
Hi Senti.
I bet the combo in humans won't be!
Call it an educated hunch...
We know that even with proneural GBM, (which may be primary or secondary), there is frequently a subsequent shift to mesenchymal!
And that shift may have already started by the time of diagnosis of a high grade glioma (whether you call it a GBM or not).
And because of intra-tumoral heterogeneity, there will be elements of both in the same tumor at the same time, because the shift doesn't happen overnight!
For these reasons, and because of the paucity of any available large data on the issue, I would not adopt a dogmatic opinion that L does not 'work' with secondary GBM's.
In the absence of anything proven to be better, if I was an NO or a neuro-surgeon or a regulator, I would not deny DCVax-L to a patient diagnosed with a secondary high grade glioma. Nor would I want to be so denied if I was such a patient!
The alternative would be to wait until a recurrence, when the tumor has likely shifted to mes. And by which time the patient is likely to have experienced significant functional deficit. Basically a lot iller.
And that doesn't make sense to me, given the benign safety profile of L.
I suppose you could hypothesise the idea that you should wait a while with such a patient, because it appears to be the chemorad treatment itself that induces or accelerates the shift to mes.
"Proneural-Mesenchymal Transition: Phenotypic Plasticity to Acquire Multitherapy Resistance in Glioblastoma"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600373/