The latest Investing Matters Podcast episode featuring Jeremy Skillington, CEO of Poolbeg Pharma has just been released. Listen here.
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Burble made the comment..
“ The results from SCIB1 have been pretty striking to say the least. Patients who to put it bluntly should be dead due to advanced melanoma are still with us today because of this incredible piece of ingenuity.”
The five year survival rate was indeed incredible. We know of at least one of the survivors who has since sadly passed away. Do we know how many on the trial are still alive today?
On the patent thou this covers the construct ie the skeleton of immunobody, and the way immunobody engages the Dendritic cell is also including in the patent .. that is very important as that is what gives Immunobody "Cross presentation" this primes the T cell with multiple signals Keeps the T cell locked onto the Dendritic cell for longer which generates that High Avidity and that skeleton can carry many epitopes so the vaccine can also carry multiple targets and importantly both MHC1 and MHC11 which means both CD4 helper T cells and CD8 T ells are activated together
Good post Burble .. i will add "the Epitopes" although cancer has millions of them and you can whittle them down to find targets that the cancer over express they are rare and often do not cause a response from the immune system so the difficulty is finding targets ........ as Burble has posted that don't cause off target toxicity and are immunogenic, that is the major reason why other vaccines fail and because they don't elicit High Avidity T cells that are capable of suppressing the cancer suppression techniques .... in other words flip the environment to pro inflammatory
Immunobody has shown it can do this ......... so combining it with products that also act on that suppression ie PD-1 or CTl4
is what will generate "Synergy" which means the efficacy of the combo is higher than each on its own
hence the trial is with Keytruda (a checkpoint)
The industry is spending Billions in this area, so what ever checkpoint is developed it should be synergistic with Immunobody
Thank you for taking the time to explain. Great post and I actualy understudy quite a bit of it the way you explained it. It's unbelievably complicated what they are doing. To actually alter at a molecular level is mind blowing to me.
Will try and get the second instalment done tomorrow - it’s been a long week and the whisky cabinet and bed are calling!
As an example, whilst not to medical grade quality, routinely during my PhD I was making 1g of DNA, overnight, in a few flasks of bacteria, literally grown on lab grade milk powder and marmite….in relative terms that’s 250 doses of the 4 mg patients, or 125 doses of the 8 mg patients for SCIB1 trial… (high profit margins). It’s plug and play (can generate more drugs and quickly), targets viruses as well as cancers (even bigger target market).
Downsides – as with any immunotherapy, especially as they are in their infancy, we don’t know long term effects of modifying T-cells. IB holds a massive advantage here over CAR-T cells though and it’s why I put my faith in this platform. It works it in a semi-natural way by utilising the immune system inside you. The pathways you are using are the same ones used normally by your immune system when they encounter something foreign. You are not removing cells, re-engineering them and putting them back inside you as you are with CAR-T. All you are doing is using natural mechanisms to make them realise that ‘this target is actually foreign – kill it.’ This has the added benefit of having limited reason for adverse effects that you may see with other drugs especially CAR-T cells which suffer from some pretty severe side effects including cytokine release syndrome, neurotoxicity and potentially death.
Talking about adverse effects the worry with any immunotherapy is that if for some reason there are off-target effects, you can’t easily switch them off. Unlike if a pill is giving you bad side effects you can stop taking it and they generally will resolve. In the case of an immunotherapy, this isn’t the case. So the choice of target is key and IMHO this is where the biggest risk to IB is. The choice of epitope to add into this construct. We put our faith in Lindy et al., to make this decision and test in the lab, in pre-clinical models etc. But we will never know just how good those models are until we start dosing them in the patient. So far, the choices have been spot on and we have seen incredible results. But that doesn’t mean the wrong choices can’t be made. So, like any drug testing, there are risks involved. We put our faith in the scientists that design, make and test these. In the case of immunotherapies, we generally have to balance that risk with the reward.
Overall, in the cancer world if SCIB1 makes it through trials to the clinic, CAR-T will be seen in the annals of history as the stepping stone between chemotherapy and IB. Covidity (covid-19 immunobody), will be seen as the end to long-term viral infections (sadly I fear excluding HIV) as we know it.
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So a summary so far – DNA vaccine (cheap to make), plug and play set-up (easy to target other things or allows you to test many different variants of constructs in parallel for very little extra cost), patent (covers any protein – i.e. both cancer and virally infected), generates a robust T-cell response from both T-helper and T-killer cells.
Currently the market by far is looking at CAR-T cells. Billions are being ploughed into this form of therapeutic both in early stage, pre-clinical, clinical and therapeutics. Initially it’s only been licenced for haematological malignancies, but soon I’m sure they’ll be targeting solids too. But why do I mention this?
CAR-T briefly, tries to do what IB does….but in a test tube (https://bit.ly/2HdQvg2). Whilst CAR-T therapies do work for most patients, they have many drawbacks. A vast cost to make, with huge potential failure rates (lack of T-cells, lack of expansion of them in the test tube, lack of ability to transform enough of them to expression your CAR, lack of T-cells in the patient to begin with, problems with rejection of the CAR-T, horrible side effects, lack of engraftment…the list goes on). A single dose of Kymriah for B-ALL treatment costs £282k (https://bit.ly/3hHDlnZ) but has a manufacturing failure rate upto 9% (https://bit.ly/3hFahxj), Yescarta from Gilead does slightly better at 1% manufacturing failure rate. But still, 1/100 doses fail to meet manufacturing standards (the patient still may get this substandard product free, but for the company all that time and energy is wasted – hence the high list price). The industry is ploughing vast amounts of cash into a system which when it works, works well, but poses a lot of points of failure. Failure which could mean a patient doesn’t get the treatment they need and so dies through no fault of their own.
Look at this now in the light of IB. With IB don’t need to generate a drug for each individual patient – you have an off the shelf drug rather than a bespoke drug (bigger target market as more people can afford the drug). DNA is stable, meaning you can have this as an off-the-shelf product potentially – if you know the target is expressed on your tumour, you could have the dose that day (CAR-T take a month to make….time that many patients cannot afford to lose). You can dose it multiple times - I would guess as many as you need, so long as the target is still present on the tumour (meaning you’re not too limited by how much you can give or how much you can make). DNA is easy to make and you can create vats of the stuff rapidly and cheaply.
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For me, the real asset I see with SCLP is the fact that it's a platform based company, with three (four if you count the Covid-19 platform) separate strings to its bow. Broadly coming at the same problem, but from multiple angles. The problem driving this research is cancer cells fundamentally are our own cells, but that have gone rogue. Rather than being treated as foreign by the body (as a bacteria or virus would), the body ignores them. So the question that is being answered here is how do we retrain the immune system to attack these rogue ‘self’ cells but in a way that has little/none off target effects, is highly effective in the way that it does it and fundamentally is workable as a therapeutic?
ImmunoBody – a DNA based platform to target a protein that is unique or highly upregulated in cancer.
It’s getting late so tonight’s musings will be on this.
ImmunoBody (and associated patents) covers a DNA based vaccine which encodes any T-cell epitope but not regulatory T-cell epitopes. In essence, the patent covers any protein which can elicit an immune response. Furthermore, DNA is incredibly easily to manipulate. You find a new T-cell epitope you want to target, within an hour you have designed and ordered the construct, within a week you’ll have it to start testing. It is if you can use the term ‘plug and play’. We’ve seen this in the fact SCIB1 (TRP-2 and gp100 targets) and SCIB2 (NY-ESO-1). It’s quick, easy and cheap to generate new vaccines. DNA synthesis to make a new immunobody construct these days is cheap (probably £120-200 all in depending on complexity of DNA sequence that have to be synthesised), so as a platform this is incredibly versatile and easy to change. Couple this to the fact the patent covers any T-cell epitope….so covers both cancer and viral cells.
Dig a bit deeper, we see the design of the vaccine is incredibly well thought out and designed such that it elicits a robust T-cell response from two T-cell components key to being able to target cancer/virally infected cells . The DNA vaccine is taken up into antigen presenting cells in one of two ways. Directly – the APC takes the vaccine up, transcribes and translates the DNA into mRNA and then into protein, whereby it is processed and presented to T-cells on MHC I/II or indirectly, is taken up by muscle cells, transcribed and translated into the protein version of immunobody (which in essence looks like an antibody). Here it binds the FC receptor on the surface of an APC, is internalised, processed….as above. Through these two slightly different pathways IB is able to generate not only a cytotoxic T-cell response but also a T-helper response too. (https://www.scancell.co.uk/immunobody).
The results from SCIB1 have been pretty striking to say the least. Patients who to put it bluntly should be dead due to advanced melanoma are still with us today because of this incredible piece of ingenuity.
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