Member Info for Burble

Have a good day LL! Enjoy the weather and I hope the ankle gets back to strength soon.

Definitely agree with your last statement. Taking life slower does give a great opportunity to enjoy the world.

RR - 'When you say "swathes of cancer patients" do you mean within the four targets or might these be extended?' - if proved in these, then it almost definitely would be extended to other targets. Vimentin is expressed in a large range of tumour types - especially those with mesenchymal origin. In addition some epithelial tumours switch from expression of cytokeratin to vimentin during metastasis (epithelial mesenchymal transition) meaning they could become targets later in disease progression.

Mesenchymal origin tumours (also known as soft tissue tumours) covers a large swathe of different types - including fibrosarcomas, neurofibrosarcomas, rhabdomyosarcoma, liposarcomas. Broadly this could be tumours of skin, soft tissues, connective tissue, muscle tissue, adipose tissue, lymphatic and blood vessels, peripheral nerves etc. So broader than the 4 we are targeting to begin with.

KonarA - 0932. Yes there can be complications associated with tumours being destroyed rapidly. In some patients you see what is known as 'tumour lysis syndrome' with rapid cell death in bulky disease. This is seen a lot in things like lymphoma and leukaemia which respond well to treatment. A lot of the time this is predictable and can be managed proactively with fluid replacement and sometimes dialysis. Though if it comes as a surprise or isn't treated, then it can be fatal. Though generally this isn't commonly seen in solid tumours (presumably because treatments aren't as good and work less rapidly due to the nature of the tumour microenvironment). TLS causes changes in metabolism where massive release of intracellular ions and metabolic byproducts occurs from the dying cells. This causes rises in potassium, phosphorus and decreases in calcium resulting in kidney injury/failure, abnormal heart rhythms, muscle cramps and weakness as well as the potential for seizures. Treatment is standardly given including intravenous fluids, allopurinol and rasburicase. careful correction of electrolyte imbalances is also required.

Very occasionally the tumour is 'propping up' various visceral walls and structures, meaning a good response may damage their integrity as the tumour is destroyed. But this is on a very case by case basis.

Something though to also point out is that the toxicity profile of a new treatment can be very different from more standard forms of chemotherapy. Therefore management of tis can be different/difficult and something the clinical teams would be aware of and keeping an eye out for.

TF

to add to Inan’s comment from the other place ‘ "However, dostarlimab can only be used on up to a tenth of colorectal cancer patients who have a genetic mutation in their tumour, which all trial participants had. . . . . . just in case anyone thinks that Moditope may be trumped".’

Dostarlimab trial shows incredible promise in patients with a particular genetic mutation (deficient mismatch repair). The PD1 inhibitor removes the brakes from the immune system and allows the bodies T-cells to target tumour cels with this particular mutation.

Moditope goes one step further, it trains the immune system to look for cells with cancer markers produced by fundamental processes occurring within cancer cells. So rather than just removing the brakes, it unleashes the immune system directly on the cancer.

In addition by being a ****tail of three separate peptides, there is very little chance the cancer cells can mutate in a way that stops all of these target peptides (vimentin or enolase) being expressed. Therefore the immune system will always be on the attack - hence the preclinical results we see.

By targeting fundamental mechanisms cancer cells use to survive (glycolysis and autophagy) the scope of patients this can potentially treat is incredibly broad as we see from the scope of the modi-1 trial.

I anticipate if Modi-1 is successful, we will see broad swathes of cancer patients able to be treated and that will place a value on moditope many times higher than what dorstarlimab is valued at. Especially if a bidding war for moditope were ever to occur.

Some interesting changes to say the least.

In addition to those mentioned below.
1) Intradermal injection for SCOV2 has gone from two 0.2 mg doses to two 0.8 mg doses or a single 0.8 mg dose (for previously infected).
Intramuscular injection has gone from two 1.0 mg doses to two 4.0 mg doses or a single 4.0 mg dose (for previously infected).

Timespan for studying each participant has reduced to 6 weeks (or upto 26).

2) Previously: The immunogenicity of COVIDITY as assessed by seroconversion - the proportion of participants who seroconvert (defined as a 4-fold change in COVIDITY-specific antibody titre from baseline).
Now: The proportion of participants who seroconvert and/or have a 4-fold increase in N ± S protein antibody titre from baseline.

3) Newly added (from original CT protocol) Exploratory: The induction of a functional humoral immune response by COVIDITY
Analysis of immune responses using intracellular staining, immune cell phenotyping by flow cytometry, cytotoxicity assays, proliferation assay, cytokine analysis, tetramer staining, and T cell receptor repertoire analysis

4) New (in parenthesis) - Participant agrees not to consume any alcohol within 48 hours prior to each study vaccine administration (and has a negative alcohol breath test prior to the first administration of the study vaccine.).

5) New - Participant has a positive result for urine drugs of abuse at screening or prior to the first study vaccine administration (Day 1) with the exception of cannabis for which a positive result is acceptable if the participant confirms recreational use, and this information is considered to be reliable in the opinion of the Investigator.

1) - dose escalation, take home - Covidity is safe at the dose level that they were initially delivering it at and possibly may achieve even better results with higher dose. We know similar was seen with SCIB1.
2) - Patients are producing a humoral response against the N protein
3) - Patients have generated both a B and T-cell response which further characterisation is needed to understand what it is targeting.
4) and 5) - potential participants having alcoholism and/or substance abuse may be part of the reason why Covidity has been slow to recruit so far.

Also remember once a patent has been posted, it means there is more freedom to talk about what it use is, what it can be used for etc. so we may see more - maybe research papers Or other things etc in the coming weeks.

‘The inventors have unexpectedly found that certain citrullinated peptides derived from Cytokeratin 8 can be used to raise an immune response against tumours including, but not restricted to, thyroid, colorectal, urothelial, stomach, liver, carcinoid, pancreatic, renal, prostate, lung, breast and gynaecological tumours.’

This is exciting! Lots of targets = increased patient benefit = bigger market = bigger value.

So I came across this post from CEPI regarding their desire to develop a vaccine library (https://100days.cepi.net/vaccine-libraries/). It got me thinking about how good a fit the immunobody platform could be for this.

Firstly, you could computationally generate a range of different 'flavours' against different viral families or individual viruses. Being DNA based, these would be easy to make, test and then store. As the immunobody platform are DNA plasmids, candidates would be easy to expand if required and generate large quantities from. Within a very short window of time, you could either have half baked vaccine candidates ready which would give a level of protection, whilst buying you time to make a strain/disease specific vaccine.

Anyway, I'll stop musing. It's a compelling thought, for CEPI, us and the world against future pandemics.

Possibly! That would be exciting (though I won’t comment further because I have absolutely zero experience in the NASDAQ/dual listing area). So will leave that to others to comment.

That’s helpful to know,

I sent them a heads up about the Wikipedia draft, but heard nothing back.

Might be worth me dropping them a line to say that the website functionality isn’t there. Would hate for them to miss other more important things.

Nada, LochinvarLass had the latest choice which passed this week. So we sit with baited breath - I wonder whether we will see June begin before we get FPD.

Interesting too that the clatterbridge has yet to open!

'What I didn't hear being mentioned was the development of an NHS AI which could be set up to spot earlier warning signs and help prevent a malady becoming a crisis. They have the historic data and given the features of most smart phones (plus addons), real time tracking for the most vulnerable is possible'

It is happening - albeit slowly. There are a number of hurdles which need to be crossed and sadly those are no easy feat. NHS digital infrastructure is not great - so how are you able to extract that data and in a format which is a) patient anonymised and b) useable. Training AI requires clean datasets to begin with, so that's a cost that either the AI companies or the NHS have to bear - it's happening in small pockets, but the NHS isn't as joined up as we are led to believe.

Then there's the issues with patient consent. You saw the backlash when it was reported that the NHS would sell our data to the likes of Google etc. There is a big distrust with this government and historically with governments around the data that are kept on us.

There is definitely a lot going on in this space with regard to AI and digital tools for early diagnosis etc. but one of the other big hurdles for implementation is actual real world demonstration that it's better than the doctors who are using it at spotting disease early etc. How do you build up the confidence in these systems without people being able to use them and learn from them and demonstrate in the equivalent of a clinical trial setting that the AI did a better job than the human? Chicken and egg.

I agree with the comments below. To add a further layer of complexity, I managed to swing by a long term friend’s house en route back from Liverpool where I’ve been for a meeting today. She’s a clinical research nurse at one of the large Manchester oncology units. In her department alone there are 7 open positions, she is working five peoples jobs just to keep the show on the road. The NHS is cut to the bone and people are leaving in droves - be that for other careers or just burnt out.

Whilst there is an appetite for clinical trials, I sense it’s not the top of any bodies priority list at the moment. Clinical staff know that without clinical trials, patients won’t see life changing medicines getting into the clinic. But when you’re short staffed, just keeping the show on the road and looking after your standard patients is tough enough, let alone adding complexities with clinical trials.

FPD will come when it comes. It may be tomorrow, it may be longer. But we’ll know about it whenever it comes. The wheels are turning, we just don’t know what speed they are. But they are turning and we are moving forward with the science and one day we’ll look back and realise how far we have come and how close to our destination we really are.

Did we ever find out what the proposed grand challenge modi-3 was going to target?

‘ Other Outcome Measures:
Exploratory: The proportion of participants who remain COVID-19 free throughout the study [ Time Frame: From enrolment through end of study; approximately 26 weeks ]
The proportion of participants that remain negative for the SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) test throughout the duration of the study.

Exploratory: The induction of a functional immune response by COVIDITY [ Time Frame: From enrolment through end of study; approximately 26 weeks ]
Pseudovirus neutralisation assay, live virus neutralisation assay, angiotensin converting enzyme 2 (ACE2) neutralisation assay.
Analysis of immune responses in participants who are SARS-CoV-2 positive’

It will be interesting to see whether some of the more recently vaccinated participants remain covid free. So that’s at least one thing this resurgence in new sub-lineages may be able to tell us.

Impact wise, with the most recent changes possibly not a huge amount. Though you may see an acceleration of people trying to get on the trial if they see an opportunity to get vaccinated with something which may be more affective then existing vaccines.

Numbers is what it’ll come down to.

Both number of covid naive patients (both natural and vaccinated) and those who have already been vaccinated.

I suspect they’ll stop/slow down when they reach 40, analyse data and then make a call. Hunch is they’ll proceed to P2/3 in the UK.

DDD/RW - true.

Though I would think that main focus of Scancell is oncology with a smidge of infectious disease and potentially autoimmune.

So logic would be you have someone with an oncology background. But CT submission and dealing with sites is pretty uniform across most target areas, so wouldn’t surprise me if the task also involves Covidity work.

Wildforce, that would be my hunch. Partner with someone to run the P2 trial, that is announced over the summer and then looking for an autumn start.

Thoughts on the new post:
Pretty standard for an organisation that is running trials. These people are important for anything from IRAS submissions, through to dealing with the MHRA and HRA. Especially when running multiple trials, you need somebody who is the main focus point. I suspect this may have been done adhoc by other members of the SCLP team.

I'm unsure exactly where the CTs are running from - I would assume the oxford clinical trials unit, but it might also be run out of the Nottingham CTU. Doesn't have to be geographically located together.

Clinical trials ongoing
- Modi-1
- SCIB1
- Covidity

Trials we can envisage may be in set-up/development/CT documentation writing stage in the background and unreported as of yet:
- iSCIB1+
- iSCIB2(+)
- Covidity Phase 2 (UK booster trial)
- GlymAbs
- Modi-2

So we have somebody managing 3 trials currently which could expand over the coming years to 8.

I’ve added additional citations, improved the wording and made the article more about LD and her life and life works, with context to Scancell, Immunobody and Moditope. There’s definitely more work to be done.

A new Wikipedia page should be set up for Scancell itself (ITM Power is a good example of how this has been written) which Lindy’s wiki can be linked to. As the current one prior to my edits seemed to be more about Scancell and not about LD as a prominent researcher.

Had a bit of a tidy up of Lindy's wikipedia page. I suspect this may be a bit of a team effort.