Adaptimmune Q&A: an alternative approach to T-cell cancer therapies – Pharmaceutical Technology

UK-headquartered biopharmaceutical company Adaptimmune is on a mission to transform cancer immunotherapy by engineering T-cells to target and destroy cancer, including solid tumours. While chimeric antigen receptor (CAR) T-cell therapies have shown great success in treating certain cancers, they have so far proven less effective at tackling solid tumours a gap that Adaptimmune hopes to fill with its T-cell receptor technology.

The company this month entered a strategic partnership, worth up to $3bn, with Roche-owned Genentech to develop both off-the-shelf, allogeneic T-cell therapies for up to five shared cancer targets, and personalised allogeneic T-cell treatments.

Pharmaceutical Technology speaks to Adaptimmunes chief business officer Helen Tayton-Martin about the companys T-cell platforms and its hopes for the new, lucrative deal with cancer drug giant Roche.

Darcy Jimenez: How does the Adaptimmune T-cell receptor platform work?

Helen Tayton-Martin: I think weve been pioneers in, first of all, being able to isolate the T-cell receptor in the first place. As its normally bound to the surface of the cell, to actually do any work on it, it was important to be able to make a stable version, a stable protein, in the first place. So that goes back to the companys heritage, right at the very beginning.

Then weve been optimising T-cell receptors once you can make them, you can adjust their affinity to make sure that they are slightly better than the natural version, so that they can actually see cancer targets. Later in life, your cell proteins change slightly, and your immune system, your T-cells in particular, and your receptors arent designed to see those subtle changes. So we can affect the affinity or the binding of a T-cell receptor to make it able to see the cancer target.

This deal [with Genentech] is based on our knowledge of T-cells, and how to make T-cells from stem cells. So thats a different platform, where we use all of our knowledge of working with T-cells to understand how to gene-edit a stem cell to take out the proteins that you want thats the important thing and then we edit in the T-cell receptors that are important. But all those edits happen while its still a stem cell, and the thing we have thats really important is a very unique platform to turn those stem cells into T-cells.

DJ: What advantages does Adaptimmunes approach have over CAR T-cell cancer therapies?

HTM: One of the key distinctions between a T-cell receptor-based approach and a CAR-based approach is the target, its what it is that the T-cell is being designed to recognise. With a T-cell receptor, youre actually designing it to recognise a small fragment of a protein thats causing or is important in the cancer development inside the cell. So its not on the surface, but what happens is the cell is always churning and breaking down proteins, and it presents fragments on the cell surface in something called an HLA molecule.

Thats what the T-cell receptor naturally binds to, and in a regular, healthy human being, your T-cells are scavenging all the time to look for those fragments on the cell surface. Normally what theyre picking up are viral proteins, peptides that are broken down and put on the surface, so thats what a T-cell receptor will see. For the vast majority of cancer proteins, things that go wrong and cause cancer are inside the cell, so there are very few that actually cause cancer and sit on the cell surface, which is why CARs are basically antibody binders, they stick to whats on the cell surface, on the top. There are vanishingly few of those that are cancer-specific.

With the CD19 CAR-directed T-cells that are on the market, that molecule is on the surface of every B-cell if youve got a B-cell leukaemia or lymphoma, its wiping out all your B-cells, so it gets rid of the cancer, but it gets rid of all the healthy cells as well. There arent very many tissues of the body where you can just wipe out the whole thing, and its not a problem.

T-cell receptors see the unique proteins that cause cancer, the fragments of them, and we can make them unique to those because we can modify the affinity, we can make sure that they just pick up the cancer cells. So T-cell receptors are really designed to spot problem cells; in particular, most solid tumours, most epithelial tumours, they are all derived from some dysregulation of an internal protein, and thats really what the T-cell receptor is designed to see.

DJ: What does this technology mean for the future of personalised cancer treatments?

HTM: Really, I think what this deal is specifically about is exactly that its the personalised approach. Every patient has got their own T-cell repertoire; they make their own T-cell receptors, they develop a tumour, and their own T-cells are reacting to it, ideally. And in fact, we know that if you can get your T-cells to see a tumour and react to it by whatever mechanism, that has a more favourable outcome for patients than lots of other approaches like chemotherapy, radiotherapy and so on.

If you want to treat every patient regardless of what targets that cancer is expressing, you dont even need to know which proteins have been dysregulated for that patient. Whatever their T-cells are that recognise their mutations, thats a way to basically enable a T-cell therapy for every patient. You get a sample of the patients tumour or the patients blood in this case, its the patients blood identify their specific, unique T-cell receptors, and then give them back to the patient.

With the off-the-shelf approach, were marrying up the front-end approach of being able to find each patient their particular T-cell receptors, and then put them into our off-the-shelf T-cells. So basically, for any patients that have a sample of their blood taken, it would pull out their own T-cell receptors, and then weve got a cell product sitting there that their receptors go into. Its customised for them, but the cell part of it is standard for everyone.

Thats the vision here, and theres a lot of fairly complex science to work through to enable that to happen so that every patient can get a cell product back. We think we know how to do that together with Genentech, and thats what the personalised part of this collaboration is focused on.

DJ: Can you talk me through the recent deal with Roches Genentech, and your hopes for the collaboration?

HTM: What we have done so far is look for a particular cancer protein that is on a lot of tumour types as in our MAGE-A4 programme, which is [expressed] on a lot of different solid tumours, and where we started to see responses to patients in those tumours.

Whats important about [MAGE-A4] is that any patient that has that protein, and has the right tissue type that presents the peptide that I talked about, can get that therapy. So thats whats called a targeted T-cell receptor therapy, but youve still got to screen for that target, youve got to screen for that tissue type that presents that peptide, so youve got to segment the patients just to make sure theyve got those two things. The personalised approach I just talked about doesnt have those screening issues.

So weve got two arms of the collaboration. One is a series of up to five targets that Genentech is interested in, and then they are producing the T-cell receptors for those, and they want to put them into our off-the-shelf T-cell products and produce a series of products that are targeted to those target proteins. Thats something that we know how to do were doing it with our MAGE-A4 programme, thats a sort of trodden path with autologous products. And we have the opportunity to profit-share and co-promote those products, because were going to be developing and commercialising products with our MAGE-A4 programme, so theyre complimentary targets.

The other half of the deal is working on this personalised approach, and thats a longer-term prospect. Its over several years that well be working together on both arms of this, hence the five-year funding commitment apart from the significant upfront, which is recognition of the value of the platform.

The two arms of the deal are very exciting, because one is adding more targets into a portfolio that we already have, and giving us the opportunity to participate and to drive those through our allogeneic platform, and everything we know about developing T-cell therapies. The personalised approach basically means that any patient could get a product down the line, and thats really why its a five-year collaboration, because although weve got some good ideas and some initial research to support what we plan to do there, its going to take time to bring that to fruition.

I think were really on the cusp of a fourth pillar, if you like, of therapeutic development with cell therapies. Showing that theyre working in solid tumours is absolutely critical, and then having an off-the-shelf approach to that, so that these therapies are less complicated or more accessible is really where its going. I like to think that Adaptimmune is right at the forefront of both components.

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28 Aug 2020

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Adaptimmune Q&A: an alternative approach to T-cell cancer therapies - Pharmaceutical Technology