CORE-NK Platform

I thought I'd try kick off the conversation about the newly optioned CORE-NK platform... so hopefully this will be a depository of research, which I hope will be challenged by those who pick up mistakes, or clarified where gaps are found... and ideally build over time as more data is released and we are able to learn more about the potential of this platform. But other than the presentations on the CORE-NK platform, the most relevant piece of reading may be the Nature publication (2019) which can be found here in full Nature IL-21 based NK feeder cells

What are NK cells and how are they different to T-cells?
Natural killer (NK) cells are part of the innate immune system, that is these exist in your body all the time and "patrol" your body to detect and destroy pathogens/viruses/tumor cells. This is important, especially when it comes to safety.

NK cells are called 'natural killer' cells because they are extremely efficient at killing virus infected cells and have some effect against tumor cells. Comparing them to a T cells is a good way to demonstrate what this actually means.

T cells are part of the adaptive immune response, which means they are targeted and are produced/replicated after a thread has been detected. At a high level, there are two types of T-cells... helper T-cells and cytotoxic T-cells (the ones that actually destroy cancer cells). Helper T-cells are what CAR-T therapies use, in that their role is to replicate after they find an antigen that activates them, and essentially turbo charge the adaptive immune response where they recruit cytotoxic T-cells, B-cells and attract NK cells and macrophages to join the battle against whatever they are targeting.

That is, T-cells are manufactured by your body in response to the detection of a threat, specifically by recognising a harmful antigen present in cells that are a threat e.g. CD-19 on blood cancers. So what happens is that a large amount of cytotoxic T-cells are made to target that specific antigen that was detected, and if healthy cells also express that antigen.. then these T-cells will kill them too.

The way T-cells work has deficiencies such as, it is relatively slow to respond (days), it can result in a cytokine release syndrome and it can lead to non-cancer cell targeting / toxicities.

NK cells however work in a totally different way. The fact they are part of your innate immune system i.e. always present, they inherently need to be very safe. Jen mentioned about NK cells have an in built fail safe system... meaning they don't kill healthy cells. What that actually means is that NK cells are naturally able to recognise healthy cells, and if they don't recognise a cell as healthy.. it assumes its a threat and instantly starts destroying it. Obviously that is a simplistic way to put it, as it is a little more complex than that (i.e. they need to also recognise ligands that activate the NK cell i.e. identified as a threat, but that activation is overridden (natural kill switch), if an inhibitory receptor is triggered i.e. it recognises it as a healthy cell. From what I could find, the way it does this is that if NK cells detect the MHC-1 molecule (present in all healthy cells), then it won't destroy that cell.

That is why NK cells are safer and can roam your body, and not kill anything and everything in its path. It needs both a trigger and the absence of a MHC-1 molecule to activate. Whereas a T-cell simply needs that trigger (antigen), and it has no fail safe mechanism.... if that antigen is present in a healthy cell, it will kill it too.

Also NK cells do not appear to trigger a rejection response from your body, which can result in a deadly disease called graft versus host disease. This is where cancer patients receive a bone marrow transplant, and a large portion of these patients immune system rejects the bone marrow transplant and starts attacking itself. Mortality in these patients where steroids are not effective, can be as high as 60-80%.

Another distinguishing feature of NK cells is that they start killing the unhealthy cells almost immediately i.e. from detection to destruction, it will be in hours. Whereas with T-cells, once the helper T cell finds the antigen, it then needs to replicate and then create cytotoxic T-cells (the killer T cellers) and B-cells (killer B cells) to do the fighting. That could take days to mount an effective immune response. Whereas the NK cells are the killer cells, and can immediately get to work.

So I've elaborated on the shortcomings of T-cells... now lets talk about limitations of NK cells.

1. NK cells only make up between 5-15% of your white blood cells.. so they are not that abundant. NK cells also do not replicate well as they are in essence part of your innate immune system, so their job is to roam your body and kill 24/7... not replicate rapidly in response to a threat.

2. While NK cells can kill cancer cells, they are most effective against viruses. Their lack of toxicity against cancer cells has been known to be one of their shortcomings.

Relating to both 1 and 2 above, the tumor micro-environment inhibits NK cell activity and expansion.. things like TGF-beta which is a cytokine produced as part of an immune response, inhibits the ability of NK cells to kill cancer cells.

3. After undergoing cancer treatment, the patients innate immune system can be severely compromised. The NK cells circulating in the patients body are likely weakened/defective, as well as the overall functionality of the immune system.

4. NK cells have a fail safe system, which can be used by cancer cells to avoid detection/destruction i.e. those that express the MHC-1 molecule will not be destroyed by NK cells.

So in essence, NK cells are really good at killing defective/unhealthy cells in small numbers... but once a cancer takes hold and have avoided detection.. NK cells are not abundant enough to destroy that cancer and can't replicate quick enough to mount a strong enough effect.


What makes CORE-NK unique and extremely promising?

This is where it gets exciting... to recap, shortcoming 1 of NK cells highlighted above is basically saying there just isn't enough of them to kill well established cancers.. especially solid cancers, which require a sustained response and lots and lots of NK cells to successfully destroy. This is where CORE-NK steps in... basically many have tried to solve this problem by trying to stimulate NK cells replication, but as noted by the Nature publication "very few clinical grade expansion platforms exists that can support large scale expansion of highly cytotoxic NK cells".

I'll summarise below what the Nature publication highlights as some attempts:

NK cell expansion using combinations of IL-12, IL-15, IL-18 and IL-21, results in approx 4x expansion at day 10. Obviously using these methods have not been succesful.

Example of successful methods include expansion methods using irradiated accessory cells as antigen-presenting 'feeder' cells lead to up to 2,300x by day 17, and Epstein-Barr virus-transformed lymphoblastoid feeder cells which result in similar robust expansion for 2-4 weeks before the NK cells become ineffective. However these more successful methods of NK expansion are already licensed and IP-protected to a single institution.

So even with successful technologies, it appears the NK cells only remain useful/active for 2-4 weeks.

What has David Wald been able to achieve? CORE-NK had on average over greater than 10,000x expansion at 5 weeks.

If that wasn't enough, shortcoming #2 on NK cells 'less than impressive' ability to kill cancer cells... well CORE-NK expanded cells are enhanced and result in a more effective cancer killer NK cell (when trialed with human cancers in mouse models), and will be a highlight if it is shown to be effective in humans which will read out its phase 1 results in 2022.

Furthermore, the next step CHM are taking is to further enhance CORE-NK and create Next Gen CORE-NK cells which make them even more effective at killing cancer cells. Things such as introducing TGF-beta inhibitors, which will make NK cells more effective at killing cancer cells. Use of non viral vectors, which are not only cheaper and easier to produce... but also safer on patients with less side-effects.

What does this mean exactly? Because NK cells are inherently safe (body doesn't reject it, has an in-built fail safe system to not kill healthy cells and doesn't result in a cytokine release syndrome), and now enhanced NK cells can be produced in large quantities from a single healthy donor.... this goes to addressing point #3 as well as a larger issue in that autologous (patient derived) treatments can take over a month to prepare and start treatments (such as CAR T therapy). But on top of the time saving, the ability to introduce NK cells from a healthy donor means that they are not damaged or effective, rather they are in prime condition and ready to destroy the cancer.


Why CORE-NK is synergistic with Chimeric Therapeutics?

Put simply, Dr Wald's work has focused on enhancing the NK cell. Overcoming shortcomings such as proliferation/expansion/survival of NK cells, and the ability of NK cells to kill cancer cells.

While Dr Wald's CORE-NK cells may be injected into a patient in sufficient quantities and once cancer cells are found they are effective at killing them, and/or releasing cyokines to recruit macrophages and cytotoxic T-cells to help kill cancer cells.

All of this is useless, if the NK cell doesn't detect the cancer cell for whatever reason... either its doesn't recognise a ligand that is foreign, or the cancer cell has 'healthy cell molecules' which trigger the fail-safe and the NK cells doesn't activate.

So this is where CHM is developing NK-CAR, which is going to use the next generation CORE-NK cells, combined with the CAR receptors i.e. CLTX, CDH-17 and an undisclosed target.

This basically means that the next generation CORE-NK cells are not only enhanced killers, but now they are also equipped with an advanced homing device which directs them straight to the target cancer cells!

So not only is Chimeric able to create a well tolerated, fast acting, targeted cancer killing machine with an in-built homing device and safety kill switch... this CORE-NK platform provides Chimeric with an off the shelf / allogeneic platform which is really the gold standard in terms of medicine. Not only is it cheaper and easier to manufacture, it is derived from a healthy donor, able to be fine-tuned and quality tested for a consistent effect.. ultimately it will make available a high quality and highly potent treatment to patients on the spot without delay, which means it takes away the opportunity for the cancer to grow for another month and possibly making it impossible to treat. As well as the chance that treatments such as CAR T failing i.e. the final product after culturing doesn't meet quality control standards, and they have to start again!

Understandably this is still a long way away from an investment point of view... but in the grand scheme of things, the fact that Chimeric could put this together... and start working on it now, means that while we progress on the CAR-T front and prove out CLTX and CDH-17 as effective targeting domains... in the background we would have already been working on the next paradigm shift and be years ahead of competitors.

I think transformative is a very appropriate way to describe the CORE-NK platform that our management team have managed to get a hold of. Combined with our existing assets, I believe we have something very special. This company is striving for cures for cancer... not prolonging the lives of cancer patients... the assets they've put together, are all aiming to cure cancer... and with this CORE-NK platform, Chimeric are now targeting 10+ diseases across solid and blood cancers...

Something I also really appreciate about Chimeric, and what distinguishes it between other companies is... firstly, Chimeric are aiming to cure cancer patients.. the bar is extremely high, and the intent is genuine... the vision is captivating. Management have acquired assets that have that curative potential... so even if it falls short, it's still going to be a huge leap. Aim for the stars, land on the moon type of thinking. But who knows, they may just reach the stars...

Also, I mentioned it above.. but it is actually very important when it comes to a company listed on the ASX. And that is, the portfolio / pipeline is synergistic. Compare it to the likes of RAD, which I had high hopes of being a CHM like company that PH put together... but to be honest, it's nothing like it. It really feels like PH stitched that company together, and while each asset has potential... they are not synergistic at all... you've basically got four businesses stitched into one, so to understand the one company.. you need to effectively invest the time it takes to understand four companies! That's not going to work very well as the investors you want (LT high conviction) will be a niche group of investors who really buy into the technologies... not saying they don't exist.. but they are going to be niche. I think that's why RAD's IPO totally flopped, and unless they release ground breaking data... the large proportion of the investor base is going to be largely clueless as to why exactly they are invested into what feels like a bit of a Frankenstein of a company IMO!

Compare that to CHM which has a CLTX CAR T, a CDH-17 CAR T.. both targeting solid tumors... using the same base CAR technology, one is a 2nd gen (CLTX) and the CDH-17 is a third-gen. Then you have the CORE-NK platform, which is a different technology, but is synergistic with both the CLTX and CDH-17 CAR, in that NK-CAR's of both of these can be created into stand alone assets and/or used in combination therapies.

I haven't even mentioned the possibility that large pharma are going to hear about our next generation CORE-NK platform, and they'll ask for us to create their own NK-CARs using targets such as CD-19 or any other antigen targets they want to explore.

A$90m market cap.

IMO when you find a company with such potential... and the share price drops, when the fundamentals remain or improve... it should really bring a smile to your face.. it literally feels like the car or thing you've had your eye on buying is on sale... that is literally how I feel about this company.

Goodluck all