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Salim Dhanji, chief executive and co-founder of ME Therapeutics, spoke with Onyx about turning the tumour's most abundant immune cells into a delivery route for mRNA — and why in vivo CAR could bring cell therapy within reach of a checkpoint inhibitor's price.
Could you start by introducing yourself, and summarising the outcome you are trying to reach for patients?
I'm one of the founders and CEO of ME Therapeutics. I'm an immunologist by training, so I've spent the last 25 years of my life studying the immune response to cancer and autoimmune disease. I have a PhD from the University of British Columbia and did a fellowship at the University of Toronto at the Princess Margaret Cancer Centre.
Over the last 10 years or so, when immuno-oncology — drugs that work by activating your immune system — started to hit the market and oncologists started to see the value of those drugs, we realised there were going to be challenges coming up for the efficacy of certain drugs. One of those challenges was going to be the tumour microenvironment: the really suppressive nature of tumours, and how they actually prevent immune responses from happening.
So we decided to form ME Therapeutics really to solve that challenge — to overcome immune suppression in the tumour microenvironment, and allow a patient's own immune system to go and fight their cancer. The therapeutics we're developing will work on their own to treat cancer, but can also be combined with other drugs that work through the immune system, in a combinatorial fashion.
Approved CAR-T therapies can cost hundreds of thousands of dollars per patient, and take weeks to harvest a patient's cells, engineer them in the lab and ship them back. Using the body as the factory instead, how do you think that would affect the wider cancer treatment economy if it became mainstream?
It's definitely the direction this type of treatment is headed. We're really moving away from ex vivo manufacturing to in vivo manufacturing, where you can inject a patient with a nanoparticle carrying an mRNA or other nucleic acid modality that encodes the chimeric antigen receptor. You deliver that with a simple infusion and have the patient's own body be the bioreactor that makes the drug, so to speak.
Obviously it improves accessibility greatly for patients, in that you can do it with a simple infusion rather than having to go to a specialised cancer centre and have your cell therapy manufactured. It reduces the timeline for treatment, so patients can get treated faster — but the cost should also come down substantially.
Conventional ex vivo therapy is probably in that half-a-million-dollars-per-patient range, plus the costs of hospital care. Whereas — and again, nothing's been approved yet — I would expect the cost of an in vivo CAR therapy to have the potential to come in closer to the range of a standard immuno-oncology drug like Keytruda, rather than the cost of conventional CAR-T therapy. I think that's the goal: to really improve accessibility and speed, and be able to treat more patients.
The STING pathway is validated, but historically very hard to drug in solid tumours. How is your approach different to what has been tried in the past?
This is really where we saw the biggest advantage to mRNA-based drugs — the ability to deliver the mRNA cargo directly to the tumour microenvironment.
ME Therapeutics was founded to target an immune cell type called myeloid cells. The ME actually stands for myeloid enhancement. These myeloid cells are your macrophages and dendritic cells, the immune cells that scavenge particles and viruses from the blood and from the circulation. But they are also the cells that make up a large proportion of solid tumour masses. They're intricately intertwined with the cancer cells, and they play a role in suppressing the immune response. The interesting thing about those cells is that they're also the ones that take up these nanoparticles and express the cargo.
So for something like STING — or any what we call a therapeutic mRNA target, where we want to express a protein that could potentially shift the tumour microenvironment, and especially the function of these cells within it — we could deliver it via mRNA in a nanoparticle that gets delivered specifically to the tumour. It gets expressed by these cells, and it either eliminates them or reprograms them to actually support an anti-cancer response rather than suppressing it.
STING was one of the ones we found really interesting, because it's an important pathway in immuno-oncology: it has been validated as important for creating inflammation in the tumour. Creating inflammation really signals to your body that there's something happening here that we should go in and see, and try to figure out a way to attack it. A lot of tumours are cold, in the sense that there's no pre-existing inflammation, and activating STING actually leads to a shift from a cold tumour to a hot tumour, where you have inflammation.
STING itself has been tricky to target, because the small molecule drugs that were developed and clinically tested had systemic toxicity. The pharmacokinetics weren't ideal for systemic delivery, so in a lot of cases you had to do intratumoral delivery of the STING drug. So you have those side effects of toxicity, but you also have patient-to-patient variability in the STING gene itself — not all patients responded to the same agonist. So while that pathway is known to be important, it's been difficult to target.
What we decided to do was use targeted delivery of an mRNA that directly encodes STING in the tumour microenvironment. We use nanoparticles targeted to be delivered to the tumour microenvironment; they encode STING; STING gets expressed in the myeloid cells and creates the inflammation that we need. The other nice thing is that we can manipulate the mRNA itself to prevent expression outside the tumour microenvironment. We can de-target areas like the liver, where you may have some toxicity, and shut down expression there. We can manipulate the untranslated regions of the mRNA to have longer expression, or shorter expression, or even cell-specific expression.
So we feel like mRNA-based STING delivered via lipid nanoparticle overcomes the potential for systemic toxicity, but also allows for targeted delivery in the tumour, where you want the activity.
Microsatellite-stable colorectal cancer does not currently respond well to immunotherapy. Why was that a good starting point for you?
I think the unmet need is just so large. We wanted to go after something that was clinically relevant and would have a big impact on patients.
The dogma is that MSI-high — microsatellite unstable colorectal cancer — has a lot of genetic mutations. But it only makes up about 5% of metastatic colorectal cancer cases. That MSI-high subtype is currently treatable by drugs like Keytruda, which are checkpoint inhibitors that activate an immune response, because those tumours are hot and have a lot of mutations, so to speak.
What's interesting is that there was a paper out of The Lancet showing that STING activation, or STING activity, correlated more strongly to responses to checkpoint inhibitors in colorectal cancer than the mutational burden did. So we feel that in microsatellite-stable colorectal cancer, if we can activate STING and create inflammation in the tumours, we can potentially make those tumours immunogenic and amenable to an anti-cancer response.
What is it like being a small company doing early-stage science, with long research timelines on one side and the short horizons of public markets and investors on the other?
It's definitely a challenge. What we're doing at the end of the day is rewarding, in the sense that we're helping patients, hopefully, one day. We've all got people around us who are experiencing cancer or have experienced cancer, and we're lucky that we have this opportunity.
One of the biggest advantages of mRNA is the speed at which we can move. We can go from an idea to actually being able to manufacture a drug within weeks. It's not like the past timelines, where it used to take months or years to develop a drug that was actually testable. So it does speed up the early stage of the drug development process, and it reduces the cost significantly. That allows us, as a small company, to do more research that's meaningful, and advance it to a point where we can get it into the clinic quickly.
The other advantage of mRNA and lipid nanoparticle delivery systems is that they've now been clinically tested to probably the highest degree, because of the COVID vaccines. And the mRNA modality itself is inherently safe, because it's transient in nature. You're never going to have the genotoxicity, because you're not manipulating the DNA of a patient — you're providing an mRNA that only lasts for a few days. So the safety bar is lower in terms of being able to get these drugs into patients quickly, and the speed of developing those drugs is faster as well.
At the end of the day we still have to run human clinical trials, which are costly and time consuming. That's really where most biotech companies start to hit difficulty, because the scale of financing you need is a multiple of what you needed for the preclinical discovery side. The last five years were challenging, in the sense that the biotech market was in a bit of a lull. But what we're starting to see now is a lot of excitement around these modalities, and money starting to flow back into the space, which is exciting.
How big is the team at the moment, and are you based exclusively in Canada?
There are 10 of us currently, so we're pretty nimble and we like to move quickly. We're all out of Canada — we're in Vancouver, British Columbia.
We work with a lot of world-class partners. We're not trying to be the experts in mRNA manufacturing, or the experts in lipid nanoparticle development — we work with world-class partners who have that expertise. We're the experts in the biology and the immunology of what we want to do. We know what we want to target and how we want to target it, and then we work with those partners to develop those drugs.
As a smaller company we also rely a lot on consultants rather than full-time employees. At the higher level, where you only need someone a couple of times a week, it's more cost-effective to structure the company that way. Having said that, as we grow and move to the clinic, it does entail a higher level of hiring as well, and having more of that expertise in-house will be important.
How many programmes do you have running, and what is it like balancing them across a relatively small team?
We have two programmes on the go currently that are being advanced to the clinic — the therapeutic STING mRNA programme, and an in vivo CAR programme.
Because of the modality, what we learn from one experiment is actually translatable to another. You're using the same delivery system and the same mRNA-based modality, so a lot of the studies overlap with one another, and what we learn in one informs the other. Two programmes, with our team the way it is right now, is completely manageable. Obviously if we need to do certain studies faster, sometimes we outsource to a CRO that can run certain animal studies concurrently with what we're doing in-house. That type of approach works well for us.
Over the next 12 months, what are the major milestones you are hoping to hit?
Over the next 12 months, our goal in the STING programme and the in vivo CAR programme is to basically lock down our mRNA formulation in the lipid nanoparticles. We've been working with a couple of different partners on the LNP side, trying to figure out which one is ideal for both of those mRNAs.
Then the hope is to lock down the formulation and have a pre-IND meeting with the FDA, or a pre-clinical trial application meeting with Health Canada, to advance both programmes. If we have the funding to do both, we'll do both. If not, we'll choose one — but advance a programme to the clinic.
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