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12th August 2024
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.
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.
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.
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.
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.
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.
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.
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.
19th June 2023
The use of base-edited chimeric antigen receptor (CAR) T cells with a specificity for CD7 could become a therapeutic option for children with relapsed T-cell leukaemia, according to the interim findings of a recent phase 1 trial.
A potential problem with CAR T cell therapy is that since both the CAR T cells and the malignant T cells share the same antigen target, there is a risk of fratricide or self-killing of the CAR T cells. One solution is to use base-edited universal and hence ‘off-the-shelf’ CAR T cells. The base-editing process involves making changes to single letters of DNA code, which stop genes being expressed without having to make a cut to the chromosomes.
In the current study, published in the New England Journal of Medicine, researchers investigated the safety of these edited cells. They used base editing to inactivate three genes encoding for CD52 and CD7 receptors, as well as the β chain of the αβ T-cell receptor. Next, they added a CAR, which recognised the CD7 T-cell receptor on leukaemic T cells. The final base-edited CD7-targeted CAR (BE-CAR7) T cells were then given to three children as an infusion.
The first patient receiving the BE-CAR7 T cells was a 13-year-old girl with relapsed T-cell acute lymphoblastic leukaemia. After 28 days, it was found that BE-CAR7 T cells were the major circulating mononuclear cells. She then received a reduced-intensity (non-myeloablative) allogeneic stem cell transplant from her original donor, with successful immunologic reconstitution and ongoing leukaemic remission.
The other two patients receiving BE-CAR7 T cells had less successful results. One died of a fatal fungal infection-related complication, whereas the other patient underwent allogeneic stem cell transplantation while in remission.
The researchers suggested that these interim results support further investigation of base-edited T cells for patients with relapsed T cell leukaemia and are aiming to recruit 10 children for the initial cohort.
1st February 2023
Yescarta (axicabtagene ciloleucel) is a CAR-T cell therapy that has been approved by for use by NICE in adult patients with relapsed or refractory diffuse large-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) who have already received two or more lines of systemic treatment.
Chimeric antigen receptor T-cell (CAR-T) therapy is a form of personalised immunotherapy that utilises the patient’s own immune which are modified and designed to destroy cancer cells. DLBCL is a non-Hodgkin lymphoma (NHL) and while in the UK alone, there are around 14,200 annual cases of the NHL DLBCL accounts for around 40% of all NHL cases or roughly 5,500 patients. In contrast, PMBCL is much rarer, accounting for 2 to 4 % of all NHL cases (around 330 cases in the UK).
Following initial chemotherapy, up to 45% of those with DLBCL require a second-line treatment such as a stem cell transplant and of these, around 50% ultimately relapse. Moreover, it has been estimated that only 60% of patients will survive for longer than 5 years after their diagnosis.
The decision to approve yescarta was based information from the cancer drugs fund, which showed that a total of 318 patients received treatment and showed a median overall survival of those given axicabtagene ciloleucel was 28.5 months and 45% of people were alive after three years.
The full guidance issued by NICE is expected to the published at the end of February 2023.
5th September 2022
Roberta di Blasi MD PhD is a haematologist at Saint Louis Hospital in Paris where she is a specialist in CAR-T cell therapy for lymphoma. Hospital Healthcare Europe had the pleasure of hearing her thoughts and perceptions on CAR-T therapy and its role in treating patients with lymphomas.
Prior to her appointment in Paris, Dr Roberta di Blasi completed her residency in haematology at the Catholic University School of Medicine, Policlinico Universitario Agostino Gemelli in Rome. Towards the end of her residency, she moved to Paris, initially working at CHU Henri Mondor in Créteil, where she became involved in bone marrow transplantation and acute leukaemias and developed a special interest in infections among haematology hosts. In 2018, she moved to Saint Louis to take part in the CAR-T cell project.
Saint Louis is a large, specialist haematology hospital with seven wards dealing with different haematological malignancies. Dr di Blasi is part of a team of seven clinicians, of whom two are based in the outpatient or day-care centre, caring for patients with lymphoma and chronic lymphocytic leukaemia. The unit has 16 beds and treats patients with chemotherapy and CAR-T cell therapy. It is a busy department, which, according to Dr di Blasi, took care of 661 patients, including 450 new patients, in 2021.
Dr di Blasi described how CAR-T therapy is ‘a form of immune therapy that makes use of the patient’s own T lymphocytes that are engineered to express an antigen that can recognise a target in the tumour cell.’ Although this target can vary depending on the pathology, she explained that ‘with lymphomas, our target is CD19, which is expressed on the cell surface of lymphomas.
Consequently, the T cells are modified to express a receptor that can recognise the CD19 on tumour cells, link to the tumour cell, and ultimately destroy it.’ Dr di Blasi explained how CAR-T therapy is a relatively new approach to the treatment of lymphomas, but while it was only introduced into clinical practice in Europe in 2018, the technology had been investigated in clinical trials for a much longer period of time prior to this.
Dr di Blasi said that her own interest in CAR-T cell therapy began in 2017 when clinicians at the hospital became more attracted to the technology, especially for patients with refractory malignancies. Given her prior experience and knowledge of allogenic bone marrow transplantation, she believed it was a natural fit, particularly as there are some complications that can arise from CAR-T cell therapy that bear similarities to those experienced by patients undergoing allogeneic bone marrow transplants. And she remains fascinated by the technology to this day.
Although her department does have strong links to the pharmaceutical industry and participates in clinical trials, an equally important part of its work involves the examination of the findings held in a national patient registry. The registry (termed DESCAR-T) collates data from patients across France and enables a much greater understanding of the impact of real-world experience of CAR-T cell therapy.
In addition, other areas of research within the hospital include basic biological science and translational research, which are designed to better understand CAR-T.
Although diffuse large cell B lymphomas and the family of related lymphomas are treated with CAR-T cell therapy, Dr di Blasi pointed out that ‘recently, the centre had received authorisation to treat mantle-cell lymphoma and follicular lymphoma’.
Dr di Blasi felt that the patient registry outcome data, in particular, treatment efficacy seen in real-world data derived from registry data, are comparable to that observed in the clinical trials, adding that the extent of toxicities was probably lower with the registry data, which was likely a reflection of how clinicians were better able to manage these adverse effects in practice.
Nevertheless, she stressed that because the production of products differed, it was not always easy to compare the effectiveness seen in the trials with the registry data although, broadly speaking, the two datasets provided similar results.
Although a novel and promising therapeutic approach, Dr di Blasi explained that CAR-T is not currently a first-line treatment option and that her hospital is only authorised to use the therapy third-line after two unsuccessful chemotherapy regimens.
She mentioned how the department currently uses two CAR-T cell products aggressive B cell lymphoma or transformed follicular lymphoma. Despite the constraint of having to use CAR-T cell therapy third-line, this might change over time, and she noted that clinical trials are starting to report on the value of CAR-T cell therapy as a second-line option in either refractory patients or in those who relapse within the first year of chemotherapy.
She also added that ‘axi-cel CAR-T cell therapy will hopefully be used as a second-line treatment for patients with lymphomas who relapse within the first year of treatment as well as refractory patients and hopefully, by the end of the year, axi-cel will be available for follicular lymphoma too.’ She revealed how the department is likewise eagerly ‘waiting for liso-cel (another CAR-T cell product) to be available for large-cell B lymphoma as well as some other entities, such as transformed marginal zone lymphoma, that were not covered by the older CAR-T cell products.’
Although CAR-T cell therapy makes use of a patient’s own cells, Dr di Blasi explained that because the cells undergo modification, it is designated a ‘product’ and therefore subject to all the standard regulatory approvals required for drugs.
Dr di Blasi explained that in her department, after a single infusion, patients were monitored for the first 10 days and, if there are no problems, discharged home but contacted daily until day 21. After 28-30 days, patients revisit the centre for efficacy assessment by a clinician.
Following this, patients are reviewed after three months, as any relapse is likely to occur at this point, and then every 90 days. She described how there were no specific criteria for choosing CAR-T cell products and this relied solely on the availability of the manufacturer to produce the product.
In cases where CAR-T cell therapy was ineffective, patients would not be switched to an alternative CAR-T cell product because, as Dr di Blasi clarified, ‘one route of escaping the treatment – that is, therapeutic failure – is due to loss of the antigen and because the target is the same, there is little point in switching to another CAR-T product.’
Dr de Blasi outlined how she has seen some remarkable results for CAR-T cell therapy, noting how ‘we have seen response rates in real life of 40-60% and are comparable to those seen in the clinical trials.’
Dr di Blasi described how after a few years of clinical experience with CAR-T cell therapy, clinicians are now better able to identify specific risk factors, both clinical and biological, such as high tumour burden, that negatively affect the response to CAR-T cell therapy. Using this knowledge, she thinks that ‘for some patients, it might be logical to conceive CAR-T cell therapy earlier in the therapeutic line.’
She mentioned that the ZUMA-12 trial has produced some remarkable findings. This is a Phase II, multicentre, single-arm study evaluating axicabtagene ciloleucel as part of first-line treatment in patients with high-risk large B-cell lymphoma or with an insufficient response after two courses.
As a result, she thinks that ‘the therapeutic strategy might change according to the clinical features at diagnosis for the patients’. However, she felt that in practice, third-line CAR-T therapy would be best suited to those patients with limited disease who are likely to respond well to the treatment.
One important and limiting factor to the greater use of CAR-T cell therapy is cost. Currently, Dr di Blasi said, ‘the total hospitalisation costs for one patient receiving CAR-T therapy is approximately €480,000’. Despite this, she pointed out that health economic studies have been favourable for CAR-T cell therapy, especially if the patient goes into remission and that, currently, ‘the balance is still in favour of CAR-T cell use’.
A further limitation to wider use was that ‘not all centres are fully certified to administer CAR-T cells’, with currently only around 31 centres being able to provide the treatment in France. An important part of the CAR-T programme, therefore, is education and involved visiting and discussing the specific patient referral criteria with non-accredited sites.
Dr di Blasi described how ‘the two well-known side-effects of CAR-T therapy – at least the ones that we have been concentrating on – are cytokine release syndrome and neurotoxicity syndromes, and these can vary substantially depending on the pathology being treated, the CAR-T cell product and even the different clinical trials.’
With the severity of these adverse effects graded on a scale from 1 to 5, Dr di Blasi mentioned that ‘grade 3 or higher [adverse effects] can vary from 8-10% and up to roughly 30% for axi-cel and from 2% to 20% for tisa-cel. Liso-cel, for which there is currently less real-world data, also has a favourable toxicity profile’.
Nevertheless, with greater clinical experience in using CAR-T cell therapy comes a better understanding of how best to manage these adverse effects. Despite advances in the management of the two key side-effects, Dr di Blasi feels that a better understanding of other emerging adverse effects was still required.
This included cytopaenia, for example, which might affect up to 10% of patients after one year, as well as the risk of infection and hypo-gammaglobulinaemia. Finally, she revealed how there is an ongoing continuing debate over whether autologous stem cell transplantation after second-line chemotherapy is more toxic than CAR-T cell therapy.
Furthermore, Dr di Blasi explained that the decision over whether to use CAR-T cell therapy for a patient was complex and involved a consideration of many different factors, but the existence of treatment algorithms had been of great value to clinicians.
Dr di Blasi thinks that immunotherapy would be the next step in the management of patients who fail to respond to CAR-T cell therapy and does not believe that such patients would benefit from further chemotherapy, a point already proven in trials. She added that in some tumours, if a second surface antigen – CD20 – is still expressed, then immunotherapy can help.
First and foremost, over the next five years, Dr di Blasi hopes to see patients with the longest possible remission and with no, or very few, long-term side effects. Future developments might enable a reduction in the level of side effects through alteration of the receptor on the CAR-T cells.
As she explained, ‘we know that toxicities are partially linked to the structure of the receptor on the surface of the CAR-T cells and to the expansion profile, so modification of this structure might lead to less toxicity, and we already have three available products which have different toxicity profiles’.
While modifying the receptor might be possible, this approach is not guaranteed to lessen the incidence of adverse effects as there are many other factors that can affect an individual’s risk of adverse effects, including the number of T cells infused and the microenvironment of the patient’s tumour, both before and after infusion, and such effects are not always predictable. In addition, she added that much more work is needed to understand why some, but not all, patients are prone to cytopaenia.
Although CAR-T cell therapy targets a particular antigen, Dr di Blasi thinks that it is theoretically possible to deploy the technology in the treatment of any form of cancer, including solid tumours, provided that a discriminatory antigen can be found, and this is an area of ongoing research. One possible therapeutic area she would like to see CAR-T cell therapy used is in the treatment of T-cell lymphomas.
Dr di Blasi concluded that CAR-T cell therapy has been a major advance in the treatment of lymphomas, but there was still much to learn, not just about the technology itself, but also about how it affects patients and what might be achieved in the coming years to maximise the benefits and minimise the adverse effects the patients in her care.
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