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 and 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 leukaemia 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.
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 (NIHR) 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).
