This website is intended for healthcare professionals only.
Take a look at a selection of our recent media coverage:
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.
12th April 2024
Tisagenlecleucel (brand name Kymriah) has been recommended for routine rollout on the NHS by the National Institute for Health and Care Excellence (NICE), its manufacturer Novartis has announced.
Final draft guidance for the treatment, which has been available through the NHS Cancer Drugs Fund (CDF) since December 2018, recommends tisagenlecleucel for children and young adults up to and including 25 years of age who have B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse.
A chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel is administered as a one-off infusion into the blood stream.
Dr Sara Ghorashian, consultant in paediatric haematology at Great Ormond Street Hospital for Children NHS Foundation Trust, said: ‘During its time in the CDF, tisagenlecleucel has changed the way in which people with relapsed or refractory B-ALL have treatment.
‘It offers a chance of durable remissions and prolonged overall survival for people who often have no other option. The CDF has enabled us to build robust real-world evidence and I’m delighted that NICE has recommended that children and young adults should continue to have access to this treatment.’
The recommendation and final draft guidance from NICE for the routine rollout of this CAR T-cell therapy is based on data collected from its use in the NHS as well as additional clinical trial evidence from three studies.
Presented to NICE as a pooled dataset, the ELIANA, ENSIGN and B2101J trials showed people treated with tisagenlecleucel lived for longer and without experiencing relapse or progression, and improved overall survival for people compared with standard treatment.
For example, the median overall survival was 48 months, compared with a median overall survival for two other standard treatments of 7.5 months for blinatumomab and a median overall survival of three months for salvage chemotherapy.
Data collected from ELIANA have been published in the Journal of Clinical Oncology.
NHS use data found that the 24-month overall survival was 72% following treatment.
According to Novartis, tisagenlecleucel was used to treat 133 children and young adults while in the CDF between 2018 and September 2023.
12th December 2022
Tisagenlecleucel in paediatric and young adults with relapsed/refractory acute lymphoblastic leukaemia retains durable efficacy over three years.
Tisagenlecleucel appears to remain effective for more than three years in paediatric and young adults who had relapsed or refractory acute lymphoblastic leukaemia according to the results of a follow-up study by an international research group.
B-cell acute lymphoblastic leukaemia (ALL) is a clonal malignant disease originated in a single cell and characterised by the accumulation of blast cells that are phenotypically reminiscent of normal stages of B-cell differentiation.
Moreover, ALL is the most common childhood cancer and has a high survival rate when properly managed.
Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and in the ELIANA trial, after a single infusion, the drug provided durable remission with long-term (12-month) persistence in paediatric and young adult patients with relapsed or refractory B-cell ALL.
Moreover, the trial reported an overall remission rate within three months of 81% and improvements in patient-reported quality-of-life scores were observed for all measures at month three after the infusion.
However, what remains uncertain is the durability of the response to treatment observed in the ELIANA trial and in the present study, researchers provided an update on the efficacy of the drug.
In the follow-up arm, 79 patients with a median age of 11 years (57% male), 92% of whom had experienced a treatment relapse, provided on-going data for a median follow-up of 38.8 months. Overall, participants had received a median of three previous lines of therapy.
In the updated analysis, the overall remission rate was 82% and the median event-free survival was 24 months. In addition, event-free survival was 44% (95% CI 31 – 57) and overall survival was 63% (95% CI 51 – 73) at three years with most events having occurred with the first two years.
Researchers estimated the three-year relapse-free survival with and without censoring for subsequent therapy to be 52% and 48% respectively. The estimated overall survival rate was 63% (95% CI 51 – 73%).
A total of 24 relapses were recorded and of which six had occurred 12 months after the Tisagenlecleucel infusion.
Interestingly, there were no new or unexpected long-term adverse events reported although grade 3/4 adverse events were seen in 29% of patients more than 12 months after the infusion. However, grade 3/4 infection rates did not increase longer than one year after infusion. Patients also reported improvements in quality-of-life up to 36 months after infusion.
The authors concluded that these data demonstrated favourable long-term safety and suggested that tisagenlecleucel is a potentially curative treatment option for heavily pretreated paediatric and young adult patients with either relapsed or refractory acute lymphoblastic leukaemia.
Citation
Laetsch TW et al. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial J Clin Oncol 2022.
7th July 2022
CAR T cells (CTC) which can be manufactured in a single day have been shown to be effective and with an acceptable safety profile, for the treatment of patients with relapsed or refractory B cell acute lymphoblastic leukaemia according to a first-in-human clinical study by a group of Chinese researchers.
In CTC therapy, the patient’s own T cells are genetically engineered and then re-infused in an effort to eliminate their tumour cells. The T cells contain an extracellular ligand binding domain which is able to recognise antigens displayed on the surface of tumour cells (normally CD19).
Nevertheless, as more clinical trials have been undertaken, it has become evident that 30-60% patients relapse after treatment, probably due to persistence of CAR T-cells and escape or down-regulation of CD19 antigen. A further problem is that the T-cell engineering process can take 9 to 14 days and up to four weeks before infusion back into the patient.
For the present study, the Chinese team developed a type of CAR T cells that were manufactured using a novel process completed in 24 hours. The final product CTC product, GC007F, was tested in patients with relapsed or refractory B cell acute lymphoblastic leukaemia and for comparative purposes, the researchers also manufactured CTCs by conventional methods.
CAR T cells and patient outcomes
A total of 21 patients with CD19+ relapsed or refractory B cell acute lymphoblastic leukaemia were enrolled and given a single infusion of GC007F cells although only 18 were included in the final analysis after the others withdrew due to adverse effects. The median peak of CAR T cells was on day 10 and the median persistence was 56 days. The GC007F cells also showed better proliferation and tumour killing than conventional CTCs.
After 28 days, all patients had achieved complete remission (CR), with 17 achieving CR and maintaining minimal residual disease negative, MRD (i.e., no disease was detected after treatment) after 3 months. Additionally, at 6 months, 16 patients maintained CR with 14 maintaining MRD negative and the longest duration at the time of writing was 29 months without the need for transplant.
In terms of safety, 95.2% (n = 20) of patients experienced cytokine release syndrome (a recognised adverse effect) and which was greater than grade 3 (i.e., severe) in 52.4% (11) of patients. Neurotoxicity developed in 6 patients and was greater than grade 3 severity in 3 patients.
Overall, eight patients underwent allogeneic haematopoietic stem cell transplantation after GC007F treatment.
The authors concluded that these preliminary data suggested that their next day GC007F cells appeared to be effective and with a manageable toxicity profile.
Citation
Zhang C et al. Novel CD19 chimeric antigen receptor T cells manufactured next-day for acute lymphoblastic leukemia Blood Cancer J 2022
16th December 2021
Ethic and socioeconomic disparities in survival outcomes have been highlighted in an analysis of newly diagnosed children and young adults with acute lymphoblastic leukaemia (ALL). This was the main finding from a study by researchers from Institute for Health Policy, Evaluation and Management, University of Toronto, Canada, presented at ASH 2021.
Health disparities are major issue for racial, ethnic, and socioeconomically disadvantaged groups and although outcomes in childhood ALL have steadily improved, disparities based on ethnicity and socioeconomic (SES) factors appear to persist.
For the present study, the Canadian team sought to identify the presence of any persistent inequities by race/ethnicity and SES in childhood ALL in the largest cohort ever assembled for this purpose. They identified a cohort of newly-diagnosed patients with ALL, ranging in age from 0 to 40 years enrolled in trials between 2004-2019. Race/ethnicity was categorised as non-Hispanic white vs. Hispanic vs. non-Hispanic Black vs. non-Hispanic Asian vs. Non-Hispanic other.
SES was proxied by insurance status: United States (US) Medicaid (public health insurance for low-income individuals) vs. US other (predominantly private insurance) vs. non-US patients (mainly jurisdictions with universal health insurance). Event-free and overall survival (EFS, OS) were compared across race/ethnicity and SES. The relative contribution of disease prognosticators (age, sex, white blood cell count, lineage, central nervous system status, cytogenetics, end Induction minimal residual disease) were examined with Cox proportional hazard multivariable models of different combinations of the three constructs of interest (race/ethnicity, SES, disease prognosticators) and examining hazard ratio (HR) attenuation between models.
Findings
The study cohort included 24,979 children, adolescents, and young adults with ALL. A total of 13,872 (65.6%) of the whole cohort were Non-Hispanic White patients, followed by 4354 (20.6%) Hispanic patients and 1517 (7.2%) non-Hispanic Black patients. Those insured with US Medicaid were 6944 (27.8%).
The 5-year EFS was 87.4% among non-Hispanic White patients vs. 82.8% among Hispanic patients (hazard ratio, HR = 1.37, 95% CI 1.26 – 1.49; p<0.0001] and 81.9% among non-Hispanic Black patients. The outcomes for non-Hispanic Asian patients were similar to those of non-Hispanic White patients.
US patients on Medicaid had inferior 5-year EFS as compared to other US patients (83.2% vs. 86.3%, HR = 1.21, 95% CI 1.12 – 1.30, p<0.0001) while non-US patients had the best outcomes, with a 5-year EFS of 89%.
There was substantial imbalance in traditional disease prognosticators (e.g. T-cell lineage) across both race/ethnicity and SES, and of race/ethnicity by SES. For example, T-lineage ALL accounted for 17.6%, 9.4%, and 6.6% of Non-Hispanic Black, Non-Hispanic White, and Hispanic patients respectively (p<0.0001).
Multivariable analysis showed how EFS among Hispanic patients was substantially attenuated by the addition of disease prognosticators and the hazard ratio reduced from HR 1.37 to 1.17 and was further (but not fully) attenuated by the subsequent addition of SES (HR 1.11).
In contrast, the increased risk among non-Hispanic Black children was minimally attenuated by both the addition of disease prognosticators and subsequent addition of SES (HR reduction of 1.45 to 1.38 to 1.32). Similarly, while the superior EFS of non-US insured patients was substantially attenuated by the addition of race/ethnicity and disease prognosticators (HR 0.79 to 0.94), increased risk among US Medicaid patients was minimally attenuated by the addition of race/ethnicity or disease prognosticators (HR 1.21 to 1.16).
OS disparities followed similar patterns but were consistently worse than in EFS, particularly among patients grouped as non-Hispanic other.
The authors concluded that there were substantial disparities in survival outcomes by race/ethnicity and SES and that these disparities varied between specific disadvantaged groups., adding that future studies are required to identify specific drivers of survival disparities that may be mitigated by targeted interventions.
Citation
Gupta S et al. Racial, Ethnic, and Socioeconomic Factors Result in Disparities in Outcome Among Children with Acute Lymphoblastic Leukemia Not Fully Attenuated By Disease Prognosticators: A Children’s Oncology Group (COG) Study. ASH Conference 2021
25th May 2021
Scientists and clinicians at UCL and Great Ormond Street Hospital studying the effectiveness of CAR T-cell therapies in children with leukaemia, have discovered a small subset of cells that are likely to play a key role in whether the treatment is successful.
Researchers say ‘stem cell memory T-cells’ appear critical in both destroying the cancer at the outset and for long term immune surveillance and exploiting this quality could improve the design and performance of CAR T therapies.
Researchers assessed the cells of patients involved in the CARPALL Phase I Study, which used a new CAR molecule known as CAT-19 developed between UCL Cancer Institute and UCL Great Ormond Street Institute of Child Health, for treatment in children with acute lymphoblastic leukaemia.
The team compared T-cells from patients who still had CAR T-cells detectable in the blood more than two years after their treatment, with individuals who had lost their cells in the one to two months post treatment.
Using a technique called ‘insertion site barcoding’, researchers were able to study the fate of different types of CAR T-cells in patients after they were given.
Corresponding author Professor Persis Amrolia, based at UCL Great Ormond Street Institute of Child Health and Consultant in Bone Marrow Transplant at GOSH, said: “Using this barcoding technique, we were able to see ‘stem cell memory T-cells’ play a central role both during the early anti-leukaemic response and in later immune surveillance, where the body recognises and destroys cancer cells.
“This suggests that this small sub-group of T-cells are critical to the long-term success of the therapy.”
Researchers say, this work indicates that the teams caring for patients could measure the types of CAR T-cells present after some someone has had their anti-leukaemia therapy, to gain an indication of whether they will be able to preserve their CAR T-cells into the future, avoiding relapse.
Professor Amrolia added: “This new insight may help us to improve our CAR T-cell therapy and work out which patients are at a higher risk of relapse and may benefit from a stem cell transplant after CAR T-cell therapy.”
Dr Biasco added: “It was extremely rewarding to see how the application of our new barcoding technology to study CAR T-cells is unveiling such important information about what happens to these cells after they are given to patients. We now plan to expand the technology we established at UCL and validate these findings in larger groups of patients.”
Co-author Dr Martin Pule said: “This research opens up new avenues to improve CAR design and manufacture, improving the performance of CAR T-cell therapy, to achieve a combination of early tumour clearance and long-term protection from relapses in patients with B cell leukaemia.”
IMPORTANT LINKS
MORE FROM COGORA
© Cogora 2025
Cogora Limited. 1 Giltspur Street, London EC1A 9DD
Registered in the United Kingdom. Reg. No. 2147432
