Member Info for Burble

Only thing I can find is the following patent entitled 'enhanced transfection' (https://patents.google.com/patent/WO2020188302A1/en?inventor=James+Dixon&sort=new) was filed a month before the Covidity programme was announced (https://www.nottingham.ac.uk/news/covid19-vaccine).

This patent then references two additional patents - one entitled 'controlled cell delivery vehicle and treatment of tumours' (https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016207638) and the other entitled 'transduction' (https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015092417).

I would speculate that LD and collaborators haven't gone from an idea for delivery mechanisms through to a clinical trial this quickly. They most likely have built upon a pre-existing technology, so whilst the needle-free aspect is still unknown, I would suspect it utilises some of these patented technologies.

GF

Difficult to say. I suspect that there most likely has been some iteration of what Nottingham have already published on. But entirely unsure.

We should find out in due course whether it is entirely new and how it delivers the vaccine.

2CV

Needle-free secrecy may be that it’s been submitted for patent protection. If anything is in the public domain, then you struggle to patent it. It’s a PITA when it comes to scientific publishing because you want to publish papers but can’t because that would invalidate your patent application. It’s also a nightmare when it comes to presenting at conferences as a PhD student/post-doc/academic because the same rules apply.

https://greatlandgold.com/wp-content/uploads/2021/07/GGP-Corporate-Presentation-July.pdf

I guess a lot of whether BioNTech are interested depends on the Moditope trial getting off the ground and showing results in patients and being able to track down the specific T-cells responsible for a patient's response.

Chester

It's definitely an exciting and data rich period that we are about to enter into. I agree that it's a watertight ship that they are sailling, but at times even just a little market update would be so beneficial. Though being kept in the dark does mean there is time for me to add to my holdings one pay cheque at a time.

Bill

Moditope is going to be an exciting trial to watch. Results I hope will be as dramatic as those seen in mice.

Looking a bit more into this, I am not worried in the slightest if this seems further ahead than the SCIB platform.

There are a number of differences but the one that really stands out is direct intratumoral delivery via electroporation. Basically, it seems that for this to work you have to inject the drug directly into the tumour, which then generates IL-12 and recruiting the immune system in that manner.

Many cancers have low immune infiltration and are what is known as 'cold tumours' for some they have high levels of immune infiltration and are known (you've guessed it) as 'hot tumours'. Basically it seems that what this IL-12 does, is make a cold tumour hot, or a hot tumour hotter. So basically acts as a molecular flag to the immune system saying 'something is wrong here, come check it out'.

So, there are obviously a differences here. You're not specifically guiding the immune system (as the Immunobody platform does) and saying 'this is a cancer because it has these flags on it's surface.
If you find anything with these flags, you need to destroy it'. Instead for Tavo you're saying 'something doesn't look right here, go check it out and if you find something suspicious you may destroy it'.

Secondly, intratumoral delivery is invasive and expensive both in technical expertise and equipment. Imagine you have a tumour in the middle of your liver. You've got to be able to deliver that drug directly into that tumour AND give it electroporation for it to be taken up and work. That will need somebody like an interventional radiologist to guide the delivery mechanisms to it's target (in 3D) and inject said drug. Great for the patient if their tumour is near the surface and easily accessible. Awful if it is buried deep in the abdomen.

Immunobody does something different. It takes the known molecular flags coating a tumour, uses the bodies own cells to present these to the immune system and then the immune system goes off and finds the tumour. SCIB1 was electroporation originally, but in the deltoid - easy to administer, no additional equipment needed outside of the electroporation kit, so could be a routine nurse administration. With the Covidity platform testing non-needle based delivery systems, if successful this will do away with needing any fancy equipment at all and instead can be delivered in the treatment setting - meaning greater patient access because more sites can offer it.

I'm not worried. Oncosec can have their time in the spotlight, but the Immunobody platform will come from behind and overtake in due course.

Ilika successful in receiving further funding.

https://twitter.com/ilikaplc/status/1413103267563941895?s=21

No RNS yet, unsure whether it needs it.

Seems there is mention of Scancell and SCIB1 in the market report.

https://manometcurrent dot com /melanocyte-protein-pmel-market-key-players-analysis-2021-to-2027-covid-19-impact/

Though it's a pay per view, so unsure what analysis there is about the company and SCIB-1.

C11

Possibly - it all does depend on how the SAHPRA is set up. Here in the UK the HRA set up a number of fast-track Covid-19 specific ethics committees for Covid trials to be able to react promptly to provide approval for trials. These would hear studies which were a vaccine, prophylactic or early treatment or diagnostic for C-19 or a study to understand the transmission of C-19 in a population. If a study fell outside this remit, then it entered into the standard approvals pathway and would be heard by one of a network of ethics committees dotted around the country. I'm unsure what the MHRA approval side of things is as I have no dealings with this side but I would assume that they would have had something similar for prompt work-up - especially as the two work very closely together here in the UK.

I therefore could see the SA equivalent doing something similar, though it also does depend on the set-up of their healthcare system and clinical trials. So they may stick to the CTC meetings listed and not deviate from that timeline. I'm unsure.

If you look at the published CTC meeting and submission dates you see the following. https://www.sahpra.org.za/wp-content/uploads/2020/11/Clinical-Trials-Committee-Submission-dates-2021_Final.docx.pdf

Date of submission to SAHPRA - 2nd July will be heard at the CTC meeting on the 12th and 13th August. Though it does state that Covid-19 Clinical Trial applications do not follow the above pre-determined submission due dates.

I'm reading that as you can submit after the cut off for a particular meeting, but it would be heard only when next CTC sits and not between.

Bojo,
If you have any further questions or anything you don't understand give us a shout.
BW
Burble

Moditope - this targets stress induced post-translational modifications.

In healthy cells proteins can be modified after production, they have embellishments added or removed to them which modulate their function. These are known as post-translational modifications. Inside cancer cells, these PTMs can be caused by cellular stress. In normal cells, there are mechanisms to prevent cellular stress which stop working or become ineffective inside cancer cells.

Cancer cells are fighting for their lives. To divide quickly, they need a constant source of energy from cells, they make mistakes copying their DNA and just generally are fighting for survival. As such, the inside of the cells aren't functioning properly as they would in a normal cell - hence proteins can become modified by stress-induced post translational modifications - this is what moditope is targetting.

Unlike the expression of receptor targets on the outside of a cancer cell in the case of Immunobody. Cancer cells can't really pick and choose when it comes to stress-induced PTMs. They happen, there's nothing the cancer cell can do to prevent them because it's fighting for survival. As such, there's less likelihood of the cancer cell changing the siPTM profile and escaping moditope.

The other benfit is because siPTMs occur predominantly in cancer cells and not in healthy cells, moditope has the potential to be hyper targetted only to cancer cells. Again, if cancers have seeded across the body, moditope should mop these up before they start growing.

So in short
- cancer treatment targets do change
- each immunobody construct targets a particular target expressed on a cell
- moditope targets the underlying cellular mechanisms within a cancer cell rather than a particular target on a cancer cell.
- each have potential benefits and drawbacks.
- each have multi-billion £££ potential
- each could target any number of cancers

Bojo.

So it depends highly on the cancer, the mechanisms for tumourogenesis and a number of other factors. Cancer is unfortunately an evolving beast and one that can be difficult to stay ahead of.

Some cancers have proteins/glycans on their surface which are relatively stable and remain upregulated in cancer initiation and progression. However for a large proportion, the molecular targets may change as the disease progresses.

An example of this may for instance be HER2 positive breast cancer. This is a cancer which has high levels of human epidermal growth factor receptor 2 displayed on the surface of the cell. This protein promotes the growth of the cancer cells and is an aggressive cancer type. HER2 treatments (herceptin for example) are effective and so progonsis is good.

Cancers can however escape treatments, such as if cancer relapses or spreads and in the case of HER2 positive BC, patients would be rescreened as the cancer may stop expressing this target on its surface. A lack of target means a therapy such as herceptin becomes ineffective.

If you can 'go hard and go fast' on a cancer, you don't give it the chance to mutate. As such, many treatments aim to do just that. They aim to remove 100% of the tumour through chemo, radio or immunotherapy to prevent the chance of escape and relapse. When a patient does relapse, this tumour tends to be different from the original one and so new therapies are needed.

Scancell's platforms have a number of different benefits. Immunobody - targetted treatment against a particular molecular target which is present or upregulated on the cancer cell surface. The benefit to T-cells is that they act like molecular scouts, so if the cancer has started seeding elsewhere across the body, if it has the target molecule on it's surface, the T-cell repertoire will mop up these seeds before they properly start growing. Immunobody is also adaptable, so in the future we may see new 'flavours' of this, targetting different commonly upregulated targets. So you may have a HER2 +ve immunobody construct, an estrogen receptor targetting construct, a GD2 targetting construct, etc. So you mix and match depending on the molecular profile of your cancer.

Moditope works slightly differently (I'm running out of space so will continue on a seperate post.)

I'm on coffee 8 today....and have been on zoom for the past 7 hours straight. It's not even Friday.

RP

Snowed under in work, meetings left right and centre with NHS England, PHE and a number of other big players in the field but some glimmers of hope that the end is in sight. Just burning the midnight oil is starting to age me prematurely.

LL

I think you've hit the nail on the head. Platforms and specifically these cancer vaccine platforms are easy to adapt to target different modalities and also have the potential to lead to more therapeutics (see the TCR work that would come out of the moditope patient T-cell screening work). They are cheap to make once a construct has been settled upon and have good shelf lives.

An added benefit to this is the fact that they are not patient specific, they are patient agnostic meaning a wider number of patients who are able to benefit. A lot of the hyper targeted medicines like CAR-T therapies (Kymriah, Yescarta etc) are patient specific and bespokely made using patient T-cells. These patient specific treatments come comes high costs and additional hurdles and relatively high levels of failure within the patient due to rejection or lack of expansion within the patient.

In comparison Scancell are patient agnostic, easily adaptable, low cost to produce and have the ability to benefit wider numbers of patients.

Not a problem in the slightest.

DTM

To be honest with you, I see no real reason why you would want to combine CRISPR technology with Scancell technology. Though I would add that CRISPR isn't my field of expertise in the slightest.

CRISPR editing is normally used to remove or change mutated genes. I would assume you are suggesting using CRISPR to directly add the construct encoding immunobody into a cell. There is no need for this to happen, as once you have initially dosed the patient with the therapeutic, the T-cells will be generated. Subsequent doses improve the avidity of these and by having breaks between doses may help improve this further.

There are a number of problems with off-target effects which gene editing has the potential for and there seems no reason to have the SCLP construct constitutively expressed.

The benefit to the SCLP platforms is that you basically are teaching the immune system to function properly and target infected or cancerous cells but doing this inside the patient. Once the target cells (cancer or virally cells infected) disappear, the primed T-cells will continue to exist and so will proliferate if they encounter the same target again in the future.

CRISPR and other genetic editing techniques may be used currently to transform patients T-cells in vitro (for the development of allogenic CAR-T cell therapies). As Immunobody has the potential to do something similar but generating targetted T-cell therapies inside the patient through the delivery of the DNA based vaccine. It effectively can side-step the need for genetic editing of T-cells used currently in CAR-T generation.