The CAR T-cell therapy tisagenlecleucel has recently been given the green light for routine rollout on the NHS to treat paediatric patients with acute lymphoblastic leukaemia. Here, Dr Sara Ghorashian speaks to Steve Titmarsh about the real-world success that led to its NICE approval; the subsequent impact on treatment decisions, patient care and clinical outcomes; and the current and future landscape of acute lymphoblastic leukaemia management.
After focusing on bone marrow transplantation as part of her specialist medical training, Dr Sara Ghorashian was curious about developing a more precise tool to utilise the immune system to fight cancer.
She studied for a PhD involving gene engineering T-cells with their own native receptors as models for cancer therapy and looked at the limitations of cancer therapy in that context. Once completed, a postdoctoral opportunity became available at the UCL Great Ormond Street Institute of Child Health in London, UK, working on chimeric antigen receptor (CAR) T-cell therapy. This too involved gene engineering T-cells, but this time with synthetic receptors, which was making headlines at the time as a potential treatment for paediatric leukaemias.
This focus on paediatric haematology brought her to her current position as a consultant in paediatric haematology at London’s Great Ormond Street Hospital.
Alongside this, she is also an honorary researcher at University College London where she has a research group looking at bringing CAR T-cell therapy to diseases that currently do not have a licensed CAR T-cell product and how to improve the effectiveness of the therapy for existing indications.
The National Institute for Health and Care Excellence (NICE) recently recommended the CAR T-cell therapy tisagenlecleucel (brand name Kymriah) for treating paediatric and young adults with B-cell acute lymphoblastic leukaemia that is refractory, in relapse post-transplant or in second or later relapse.
This was supported by pooled findings from three clinical trials: ELIANA, ENSIGN and B2101J, as well as data collected through tisagenlecleucel’s use via the Cancer Drug Fund, in which Dr Ghorashian played a pivotal role.
How has the treatment landscape of acute lymphoblastic leukaemia evolved in recent years?
Haematopoietic stem cell transplant has an important role in the management of acute lymphoblastic leukaemia, and CAR T-cell therapy was a big story as a treatment option for patients who had relapsed after bone marrow transplant.
These patients often reach the ceiling for toxicity in terms of chemotherapy and radiotherapy in the context of a bone marrow transplant. They were still relapsing and there was no option for those patients. CAR T-cell therapy – such as tisagenlecleucel – has an ability to give a proportion of these patients a curative option.
More generally, the ability to harness the immune system has been investigated over the last five to 10 years using antibodies that recruit T-cells within the patient’s own body to act in the same way as the CAR T-cells.
In terms of logistics, that’s a bit more straightforward as it’s an ‘off-the-shelf’ antibody reagent therapy and doesn’t require a specially made product for each patient, plus it’s cheaper to deliver.
At GOSH we’ve been actively involved in trying to bring this antibody therapy to the fore because, again, it provides an option for people who have hit the ceilings of toxicity or whose disease appears refractory to chemotherapy.
Part of the work we’re doing in the UK is to hopefully bring it earlier in the treatment pathway rather than being reserved for patients who are relapsing. We’re investigating ways to do that and are collecting data.
CAR T-cell therapy and bone marrow transplantation will still be there for where those approaches have failed. But we’re trying to be a little bit more selective in the patients that go down the avenue of transplantation to try and spare the toxicity of a bone marrow transplant overall.
We know, for example, that we make children infertile with some types of transplants that we give and there are impacts on growth and cognition, so where we can safely give CAR T ahead of a bone transplant then we do. For those who have had a transplant and still the disease comes back, then we can give CAR T-cells.
Please tell us about the real-world findings that prompted the NICE recommendation for tisagenlecleucel and your continuing research
We collected UK data on treatment with tisagenlecleucel from the beginning of the programme in 2018 after it became available through the NHS Cancer Drugs Fund until 2022 and then followed up those patients up for a further year.
We basically replicated the outcomes that had been seen from the pivotal ELIANA trial. Tisagenlecleucel was delivered as successfully in a UK real-world setting as in the pivotal study, which is a credit to all those involved. In fact, our toxicity profile was better because we learnt how to manage bringing patients to the treatment more effectively.
Persistence has been an issue, and this remains a key unmet patient need. On the pivotal study, persistence was good, and the main cause of relapse was a leukaemia that had escaped recognition by the CAR T-cells, which happened in about 70% of occurrences.
In our real-world study, although our number of relapses was the same as the ELIANA study, this time the main mechanism for relapse was because of failure of the persistence of CAR T-cells. The leukaemia hadn’t changed as the CAR T-cells didn’t hang around for long enough to render the patient cured.
The reasons for the lack of persistence are not fully understood, but patient factors, T-cell fitness and immune responses to T-cells can all interact to mean that CAR T-cells sometimes don’t persist long enough.
In some patients, however, CAR T-cells seem to persist for a long time. The first patient treated in the UK five years ago still has their CAR T-cells present. It’s a living drug so if the T-cells are programmed correctly then they should persist for many years – we don’t know how long but there are patients treated in the 1990s who had CAR T-cells present more than a decade later.
When you make the product, all the daughter cells will have the receptor, so you just need the clone of cells that derives from the product to persist. We don’t know enough about the science of what makes that happen – it does in some patients, it doesn’t in others – but part of my research activity is to find out what CAR T-cells need. We’ve taken CAR T-cells that have persisted long term, looked at their characteristics in detail to try and understand how they got to that state.
How do you envision the routine NHS rollout of tisagenlecleucel improving patient care and outcomes?
Tisagenlecleucel will allow transplantation to be avoided in a proportion of patients, which is a significant benefit, so these patients aren’t rendered infertile.
We hear time and time again that patients receiving CAR T-cells feel better than they have done since before their original diagnosis, which, given that in many cases it can be years’ hence is remarkable.
Quality of life can be improved greatly, and we have been able to rehabilitate patients who have experienced terribly debilitating toxicity that has meant that they can’t walk, for example, to get children back to school and parents back to work.
When it works, its brilliant, but sadly we don’t know how long the benefit will last. We’ve demonstrated that just under half of patients will need no further treatment and if we can make that 100% of all patients who get CAR T then that will be great. It’s a good way forward – much easier than delivering chemotherapy or transplant given the long-term side effects of these treatments.
To what extent do you see knowledge and understanding of tisagenlecleucel among UK and European clinicians?
Now that there are CAR T-cells for lymphoma and with other new indications potentially coming up, people are more aware of it. CAR T-cell therapy for lymphoma is now happening at many, many more centres than we deliver CAR T for acute lymphoblastic leukaemia.
So, awareness around the technology is now spreading. Soon, any centre delivering a bone marrow transplant for these conditions could also deliver CAR T-cell therapy. That means that there is a lot more expertise generally. However, for paediatric acute lymphoblastic leukaemia, there are specifics around the way that we deliver that don’t necessarily apply to adults with lymphoma.
One benefit of paediatric haematology is that because the patient load is small, we’re a very small community and so leukaemia physicians across the country speak regularly. We’ve tried to make sure there’s national access and we have a national panel that meets every other week to discuss all patients in the paediatric setting who have relapsed.
In that meeting we identify who would be eligible for CAR T alongside any other options they might have and then we discuss that again in more detail in a national CAR T meeting that also happens every other week.
Anyone who we would deem to be eligible is discussed and then offered CAR T if we think that that’s important for them. We also give advice on the other options so that the clinicians looking after them can really give the family the information that’s needed to guide them to make a decision. If they would like CAR T then they’re allocated to a centre based on distance and availability.
That’s the model that we’ve been operating for the last five years – as long as CAR T has been available. Through this process, we can make sure that the relevant treatments are offered.
Through that same forum we were able to collect the real-world data that supported the NICE appraisal for tisagenlecleucel so it’s been a really tight system that’s provided benefit for patients with acute lymphoblastic leukaemia.
Systematic discussion of all relapsed patients is only possible as a result of there being a national health system, and this does not exist in other European countries or the US, for instance.
A strength of the UK is that patient eligibility is ascertained on a national basis and recorded, and that means all patients who have access to treatment on the NHS can be tracked and every single case validated. I think this is something that the UK can be really proud of as the infrastructure is already built into our NHS.
Are there any innovations in development for acute lymphoblastic leukaemia that you’re particularly interested in?
With my mentor and colleague, Professor Persis Amrolia, we are researching treatment with dual CAR T-cells that target two different molecules on the leukaemia surface to try to eliminate the type of escape where the cancer evolves and evades recognition.
We’ve now generated a dual CAR product and we had a study that demonstrated that it eliminated the evolution of disease that could evade recognition, but, again, persistence was a problem, so he’s now taking forward that approach.
I am researching ways to make T-cells persist by improving their fitness, specifically through additional gene engineering approaches. By looking at the genetic status of CAR T-cells that do persist long term, we might be able to learn how to specifically engineer those characteristics into them in addition to the receptor.
I’m also looking at CAR T-cell therapies for diseases that don’t have a licensed product at the moment, for example, acute myeloid leukaemia.
Tell us more about blinatumomab and the developments with antibody-based therapies
As I mentioned, at GOSH, my colleagues have led national initiatives to try to deliver antibody-based therapies, initially for patients who experience significant treatment toxicity and those with residual disease following chemotherapy. We tested it in that context and then we use those data to advance the use of this antibody so it wouldn’t just be used for patients with highly advanced disease but could be brought into first- and second-line treatment.
I’m part of a UK relapse group that’s written guidelines to document the use of blinatumomab in a relapse setting, but we also use it in the frontline for patients who have disease leftover or who’ve had too much toxicity.
By collecting data, we are providing evidence that’s important to inform future study designs in which we will bring use of that antibody forward into frontline.
With this and CAR T, we are building a toolkit of immune treatments for leukaemia that may avoid the more toxic regimens which, while effective, have significant mortality and morbidity associated with them to achieve a cure.
