Despite the excitement surrounding T-cell therapy, CAR-T cells have fallen short in effectiveness against solid tumours. Oxfordshire-based Adaptimmune is one of the companies exploring T-cell receptors as a promising alternative. We spoke to the company’s chief technology officer Gwen Binder-Scholl about the science behind this challenging but exciting therapeutic area

Tell us a bit about Adaptimmune and your role.

Adaptimmune was spun out of Oxford University and the original technology centred around how to produce soluble T-cell receptors (TCRs). I’m responsible for aligning discovery and translational research with clinical outcomes for the company.

Where did the science come from and what unmet needs is it hoping to address?

The modality of T-cell therapy has evolved spectacularly over the last decade. I’ve been working in the field since the early 2000s, so I’ve seen it go from a very academic, hypothesis-driven experimental exercise to something that is really transforming patient outcomes.

Engineered adopted T-cell therapy has two main modalities. The first is using a CAR, a synthetic T-cell receptor that can only see the cell surface protein. TCRs are the natural way a T-cell sees its target, but they’re much more challenging to engineer, to isolate and to characterise, and it’s very difficult to get a TCR that has the optimal level of recognition and T-cell activation for tumour antigens.

But the original problem with being able to develop a TCR was that you couldn’t reliably reproduce a soluble T-cell receptor. Bent Jakobsen, our scientific founder, identified residues between the alpha and beta chains of a T-cell receptor in which he could design in disulphide  bonds that would enable soluble production and then high throughput characterisations and screening of  T-cell receptors.

That forms the core of our intellectual property, and once we solved that problem we were able to identify T-cell receptors against tumour targets and optimise their affinity.

What are the company’s main goals?

CAR has demonstrated to the world that adopted T-cell therapy can transform patient outcomes. The next challenge is identifying tumour antigens that are truly tumour-specific and developing adoptive T-cell therapies that can overcome the tumour microenvironment so we can replicate these stunning results in more challenging solid tumour settings. Adaptimmune is focusing on new combination approaches where we provide patient T-cells with additional genes to help them overcome these challenges in solid tumours.

People know that TCR-engineered T-cell therapy is required in order to address solid tumours. We know that even though CAR Therapy has been really successful for CD19, T-cells that are expressing synthetic CARs are not as sensitive to activation as T-cells expressing T-cell receptors. Not only with CARs are you only able to target cell surface proteins but T-cells also need more of the target in order to activate – so we haven’t seen responses against solid tumours. But at Adaptimmune, for example, in our NY-ESO programme we saw up to 60% response rates in patients with synovial sarcoma using TCR engineered T-cell therapy.

Right now we have four ongoing clinical programmes. Our flagship programme was our NY-ESO programme. That was under an option agreement to GSK, which they have now exercised, and we completed the transition in July. We now have three wholly-owned programmes. Two are cancer testis antigens – MAGE-A4 and MAGE-A10, in multiple tumour indications including head and neck, melanoma, and ovarian cancer – and the other is AFP, an oncofetal antigen, in hepatocellular carcinoma only. We’re in the process of going through the dose escalation of these programmes now and we’re expecting data to read out at the end of this year

What are some of the biggest challenges of working in this area?

The majority of tumour antigens are self-antigens, so they’re  self-proteins that are aberrantly expressed in the tumour.

The problem is that, since it’s a self-antigen, the circulating T-cell repertoire that a patient would have against these targets is very low affinity, because your immune system has developed sophisticated mechanisms to avoid attacking itself. The main mechanism is called central tolerance. Your thymus has a gene expression programme that can express virtually any protein that’s in a normal cell – so if a T-cell, while maturing, has a high reactivity in the thymus those cells will get deleted. The only cells that are circulating in a patient against tumour antigens that are self -ntigens are extremely low-affinity because they’ve been able to escape central tolerance. We think this is one of the reasons why cancer vaccines have not been
very effective.

So what we do is we take wild-type affinity T-cell receptors and increase the affinity to optimise T-cell activity. That does two things – we only increase affinity within physiologically relevant levels, but it enables recognition of the tumour.

By increasing the affinity of the T-cell receptor you’re also enabling some function in the CD4 T-cell compartment, which improves the function of the CD4 T-cells and also helps to promote the spreading of antigens, which can then target multiple antigens on the tumour and improve responses.

How has the company adapted to working in this area?

We’re unique in the sense that we have a very large, established discovery research team here. We have  145 researchers in the UK, a very established group  that has been working cohesively together for a long time.  We have multiple programmes that we’re assessing and have a robust, established clinical  development team.

For this type of therapy it’s advantageous to be a vertically integrated company. You need to have control over the manufacturing of the cells, and control over how you manufacture the vector to genetically modify the cells. You need to have a strong translational research programme so that you’re learning how your cells are behaving in patients and how the tumour changes  in response, so you can design approaches to get over that. And you need to have a pipeline of receptors. That is a key feature of Adaptimmune; we have vertical integration of all those features, and that’s why we  will be able to continually adapt quickly to what  we observe in the clinic and continue to address the  solid tumour challenge.

Meanwhile, many other academic groups and companies are starting to evaluate these second generation approaches, so it’s going to be a very exciting time for the whole field.