New CAR-T cell therapy gives hope for patients with aggressive blood cancer

A new chimeric antigen receptor T cell (CAR-T) therapy has delivered promising results in treating patients with an aggressive blood cancer, in results from a clinical trial led by researchers at UCL and UCLH.

Results from the FELIX trial, sponsored by Autolus Therapeutics and published in the New England Journal of Medicine, show how a second-generation CAR-T cell therapy, known as obecabtagene autoleucel (obe-cel), has reduced immune toxicity and persists for longer in patients – overcoming two common limitations of earlier CAR-T cell therapies.

What is B-ALL is how has it been treated?

Relapsed/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL)¹ is a type of acute leukaemia which if left untreated causes bone-marrow failure and death. Standard treatment is with chemotherapy and bone marrow transplant, but for most adult patients the leukaemia doesn’t respond to treatment or relapses. These patients are left with few treatment options and poor long-term survival.

CAR-T cell therapies, which reprogramme a patient’s immune cells to attack cancer, are transforming the treatment of blood cancers.

In the UK, a CAR-T cell therapy called brexucabtagene autoleucel (brexu-cel) was licensed for relapsed B-ALL in 2023. However, brexu-cel causes high rates of severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, side effects caused by over-activation of the immune system.

In addition, brexu-cel CAR-T cells persist for only a short period of time in patients’ bodies, leaving patients susceptible to relapse.

Obe-cel solves problems with existing CAR-T cell therapies

For the FELIX trial, patients had their T cells genetically modified with obe-cel. This treatment programmes immune T cells to make an artificial protein called a CD19 chimeric antigen receptor (CAR) on their surface, directing them to specifically recognise cancerous cells.

Obe-cel was designed by scientists from UCL Cancer Institute, led by Dr Martin Pule, to address some of the limitations of current CAR-T cell therapies.

By reducing the time obe-cel CARs engage with their target, Dr Pule hypothesised that obe-cel would cause less inflammation while clearing leukemia cells and allow the CAR-T cells to persist for longer in patients, thereby preventing relapse.

Obe-cel was licensed by UCL spinout Autolus Therapeutics following promising data in UCL Phase I studies in children and adults with treatment-resistant B-ALL.

The FELIX phase 1b-2 clinical trial assessed the safety and effectiveness of obe-cel in adults with treatment resistant B-ALL.

In total, 127 adult r/r B-ALL patients whose cancer had not responded to treatment or returned after treatment took part in the study at hospitals in the UK, Europe and USA.

The results showed that 74.7% of patients had a remission after treatment.

Using the trial data, the team estimated that after six months 65.4% of patients with r/r B-ALL would be alive and disease free if they received obe-cel, with 49.5% alive and disease free after 12 months.

Further, just 2.4% of FELIX trial patients had severe cytokine release syndrome, compared to around 24%, who received brex-ucel². 

Severe immune effector cell-associated neurotoxicity syndrome, which occurs in 25% of patients treated with brexu-cel, was experienced by just 7.1% of trial patients who received obe-cel.

Obe-cel was recently approved by the US Food and Drug Administration (FDA) based on the results of the FELIX trial.

Dr Claire Roddie, lead investigator of the FELIX trial from UCL Cancer Institute and UCLH, said: “While we have a licensed CAR-T therapy to treat r/r B-ALL in the UK, high toxicity is an issue in around a quarter of patients and lack of CAR-T persistence in the blood can lead to relapse and the requirement for more lines of therapy, including stem cell transplant.

“In contrast, our results from the FELIX study demonstrate that obe-cel can induce durable remissions with substantially fewer toxicity issues, which is great news for patients with what has historically been a very difficult cancer to treat.”

Development of obe-cel

Obe-cel was designed by scientists from UCL Cancer Institute, along with collaborators at the UCL Great Ormond Institute of Child Health and UCLH. Dr Pule leads the UCL CAR-T cell programme, which is supported by the National Institute for Health and Care Research UCLH Biomedical Research Centre (BRC).

The manufacture of obe-cel was developed at the Centre for Cell, Gene & Tissue Therapeutics, Royal Free Hospital. Clinical development in adult B-ALL was built on the ALLCAR19 clinical study, led by UCL and UCLH, and supported by grant funding from the NIHR.

Autolus Therapeutics is a UCL spin-off company founded by Dr Martin Pule which has raised over $1B, with most of this invested in the UK. Licensing of obe-cel is currently being sought from the Medicines and Healthcare products Regulatory Agency (MHRA).

Dr Martin Pule, from UCL Cancer Institute and UCLH, who is also founder and Chief Scientific Officer of Autolus, said: “Success in developing obe-cel shows what can be achieved through collaboration between UCL, its affiliated hospitals and industry.”

Obe-cel will be manufactured at Autolus’ commercial manufacturing site in Stevenage, UK, which will supply the therapy globally. 

Future of CAR-T cell therapy at UCL

Cellular therapies like CAR-T cell therapies represent a new branch of medicine which is changing the treatment of cancer patients as well as patients with other diseases like autoimmunity. Obe-cel development places UCL at the cutting edge of CAR-T cell technology. UCL and its affiliated hospitals are committed to continue developing new cellular therapeutics which can transform the lives of patients with serious illness.

Notes to Editors:

For more information, please contact:

 Dr Matt Midgley

+44 (0)20 7679 9064

m.midgley@ucl.ac.uk

Sharon Spiteri, UCLH
+44 7930 610105
sharon.spiteri@nhs.net

¹ More information is available on the Cancer Research UK website.

² All comparisons to Brexucel are based on the results of the Zuma 3 phase II clinical trial.

Publication:

Claire Roddie et al. ‘Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia’ will be published in The New England Journal of Medicine and is strictly embargoed until Wednesday 27 November 2024 at 22:00 GMT / 17:00 ET.

DOI: https://doi.org/10.1056/NEJMoa2406526

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