EXCLUSIVE INTERVIEW

Pharmafile speaks to Enara Bio

Kevin Pojasek: When you look at the field holistically, especially with cell therapy, there has been a massive revolution over the last 10 years that’s only accelerating. The challenge that we found today though, is that the majority of programmes are all exploring the same sets of targets. If you look at CAR T, for example, and I did this analysis recently, upwards of 80% of the programmes are going after the same five targets. And for TCR-T, roughly 50-60% of programmes are pursuing the same targets.

There’s a reason for that: a lot of these are novel technologies, novel cells, novel edits, and novel approaches. In order to test that novelty with managable risk, it needs to be used with an existing target. That’s all great, and we’re cheering everybody on, but ultimately, we’re aiming to get to a place where novel targets are part of the future of cancer immunotherapy. To invest in those novel targets, and to have them ready as these different platforms play out, we need to start working towards them today. Novel immunotherapy targets aren’t easy to find and validate, but once developed, are differentiated and core to the future of cancer therapy.

The reason we’re doing this is as a push to get the tremendous response rates we’re seeing in haematological malignancies with things like the CD-19 CARs, or the BCMA CARs. For example, there’s J&J and Legend’s product, CARVYKTI, which was just approved in late February, with 80% objective response rates.1 We want to try to get that level of response in solid tumours.

What we’ve seen up to date is that the best way to achieve responses in solid tumours with cell therapy is using TCR-directed approaches. This is our focus at Enara. We’ve got some interesting and novel targets that will drive broader, deeper, and more durable responses. It’s a really exciting field, and it’s evolving quickly. We think, unquestionably, novel targets are going to be part of the future solution, and now is the time to go after them.

I’ll be perfectly honest with you: it’s also fun science. It’s really interesting to be at the forefront of a new area of science, and our company and our collaborators are leading the way in the work that we do, which, although it’s hard, also makes it fun.

We’ve taken two primary approaches so far. The idea is focused on solid tumours, and on getting deeper and more durable responses for more patients with TCR-based therapy. Our lead programme is targeting a molecule called MR1, which is an unconventional T cell target.

It presents metabolites from inside the cell to the immune system, and, through sets of data published more recently, has been linked to cancer. MR1 is an interesting lever for the immune system in cancer. For us, it’s about better understanding that biology and what’s driving it, and then being able to identify TCRs from a variety of sources that recognise MR1 in a cancer-specific fashion, that don’t see normal cells. Then the aim is to turn those TCRs into products we can take into the clinic.

There’s a massive effort underway, across the board, to do that – ranging from bioinformatics to metabolomics, immunology, and around cell therapy, manufacturing, and clinical development. With a focus on product development, because it’s novel biology, there’s always a new fringe of science that’s waiting around the corner.

Another area of science to pursue is something we’ve called ‘Dark Antigens™’. These are peptide antigens presented by HLA molecules, in a more traditional T cell presentation mechanism. But what’s different about these antigens is they come from what was previously described as the ‘dark matter of the genome’, or the region of the genome that was thought to be not transcribed.

What we’ve subsequently learned, and what many others have observed as well, is that these Dark Antigens emerge from a variety of genetic dysregulations that occur in cancer. We map this biology across a whole range of tumours, and have identified a whole set of these antigens. They have a different fingerprint – there’s been a big wave of folks focused on checkpoint inhibitors and neo-antigens, looking at tumour mutation burden as a function of immunogenicity and where those new antigens appear, and where checkpoint inhibitors respond.

Here there’s a different genetic regulation mechanism: they’re epigenetically defined, and so the spectrum of distribution is very different, and provides different opportunities. Quite frankly, in potential opportunities where those other checkpoint inhibitors and neoantigens are less fruitful, we see a potential path for Dark Antigens, based on the work we’ve done so far.

It really is interesting science: these are shared across patients with a given tumour type at a fairly high rate. With a single product you can look at treating a broader range of patients, which ties back to the mission of going after these novel targets. This also brings about a broad approach: we’re focused on cell therapy and TCR-based therapy internally, but we are also believers in cancer vaccines. We have a partnership with Boehringer Ingelheim, to develop some of these antigens for cancer vaccines for various cancer indications.

One of the silver linings of COVID-19 is that there’s a much better understanding of vaccine platforms, and how they can influence human disease. There has been a slightly chequered past of cancer vaccines, but hopefully with better platforms and better targets, we can achieve better outcomes. That’s the approach that we’ve taken on our unconventional antigen front.

Today, despite the advances we’ve seen, the benefits are still only for a really small subset of patients. Even looking at the PD1 or CTLA4 checkpoint inhibitors, they can be curative in settings where there had been no cure before, especially in things like metastatic melanoma, and other diseases, which is wonderful. But there’s probably only about 20% of patients that are going to get that benefit.

Now, there are other approaches people are exploring, and therapies that are directly targeting specific mutations. There’s a lot going on. But what we really want to do as a field is try to shift that 20%, to 50% or higher, to even more patients, in a given indication. This is a whole set of convergent areas of science trying to be brought to bear on solving this problem. We have much better datasets, better access to patient material, a better ability to interrogate that patient material through single cell sequencing and RNA TCR sequencing, and a better ability look at that data through bioinformatics for a clearer sense of what’s going on in the patient, which can all be used for an informed approach.

We also have much better platforms. We spoke about cancer vaccines, but there’s also work in cell therapy, and off-the-shelf cell therapy coming with gene therapy and other editing technologies.

Finally, and again, this is what gets us out of bed in the morning, there’s novel target biology – trying to think about targets that matter in the areas of unmet need, especially solid tumours that will allow you to treat a broader range of patients than the existing targets and the existing approaches. The goal would be to get that 80% objective response rate seen with the BCMA-targeted CAR-Ts and myeloma. Being able to do that in a solid tumour would be a miracle today in all honesty, but hopefully one that’s in sight, given the advances we’re seeing across the board. Another aim is increasing the threshold of checkpoint responses, from 25-30%, to 50%, to 80% of patients benefitting. That’s where we hope this is going, and we hope we can play a small part in helping bring this benefit to a broader set of patients and their families, and society as a whole.

Unmet need really centres on solid tumours, I think. Simply getting more efficacy in treating a broader range of solid tumours, and especially ones that have low tumour mutation burden, or ‘cold tumours’ as they’ve been called. It would be great to see cancer immunotherapies, including targeted cell therapies, start to make a difference in pancreatic cancer, where, by the time you’re diagnosed, it’s often too late for these advanced therapies. One of the greatest unmet needs is probably a combination of better diagnosis, and better therapies. But I think solid tumours are the next frontier, and where we need to tackle a lot of unmet need.

There was a paper published recently by Carl June’s group at the University of Pennsylvania. June has been at the forefront of cell therapy for cancer, and the paper describes a few patients from some of their early CD19 work, where these patients have been cancer-free for 10 years – an unbelievable achievement and mark for the field, and it receives all the appropriate accolades for it.2

But what’s interesting is they’re starting to explain why. They’re able to find the edited cells they put into these patients, they’re able to see what they look like, and how they were different to the cells perhaps that they administered in the first place. From there, these learnings can be taken, from those responding patients, and integrated back into the cell therapy editing and manufacturing process. The process is about connecting that patient response with the cell phenotype driving that response, to then help create a virtuous cycle of ensuring that the cell products we put forward in the future can incorporate that learning. There are caveats to that, and different tumours are going to vary, but I think that connectivity of the clinical lessons learned, back to the product development, is really going to help try to solve the solid tumour problem with cell therapy.

In all honesty, the most exciting thing is this: we’re just getting started. We’ve seen that in the settings where it works, the most powerful therapy available is a T cell; it’s a fundamental driver of human immunity, it keeps us alive, and when unleashed in the proper way in cancer, it has a tremendous effect. That’s the reason to believe, and I think the excitement is in thinking: “That’s a great foundation to build on. How do we do it better? How do we take it to more places? How do we conquer novel and unconventional targets, and novel biology?” I think it helps knowing that there’s a great tool in the arsenal to tackle a daunting problem. That only increases my enthusiasm and excitement for going after novel biology, trying to map that onto the unmet need in the clinic.