A second-generation chimeric antigen receptor (CAR) T-cell therapy may offer a new option for patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), an aggressive blood cancer with few treatment options.
Results from the phase Ib/II FELIX trial, published by Roddie et al in The New England Journal of Medicine, demonstrated how treatment with obecabtagene autoleucel, an autologous 41BB-ζ anti-CD19 CAR T-cell therapy, leads to reduced immune toxicity and improved durability in patients—overcoming two common limitations of earlier CAR T-cell therapies.
Background
Patients with relapsed or refractory B-cell ALL receive chemotherapy plus bone marrow transplant as standard treatment, but the majority of patients will either not respond to treatment or will relapse—leaving them with few treatment options and poor long-term survival. In recent years, CAR T-cell therapies have transformed the treatment of hematologic cancers.
The CAR T-cell therapy brexucabtagene autoleucel was approved for use in the United States in 2021 and in the UK in 2023. However, this agent is associated with high rates of immune-related adverse events such as severe cytokine-release syndrome (24%) and immune effector cell–associated neurotoxicity syndrome (ICANS; 25%). In addition, it persists for only a short time in patients’ bodies, leaving them susceptible to relapse.
Obecabtagene autoleucel was developed by scientists from UCL Cancer Institute, led by Martin Pule, MB Bch, FRCPath, MRCP, to address some of the limitations of current CAR-T cell therapies. By reducing the time obecabtagene autoleucel CARs engage with their target, the investigators hypothesized that the agent would cause less inflammation while clearing leukemia cells and allowing the CAR T cells to persist for a longer time in patients, thereby preventing relapse.
Study Details
The current phase I/IIb study assessed the safety and efficacy of obecabtagene autoleucel in patients with relapsed or refractory B-cell ALL. In total, 127 adults with relapsed or refractory B-cell ALL took part in the study at hospitals in the UK, Europe, and the United States.
The results showed that 77% of patients experienced an overall remission after treatment, the primary endpoint, with complete remission occurring in 55% and complete remission with hematologic recovery occurring in 21%.
Using the trial data, the team estimated that after 6 months, 65.4% of patients with relapsed or refractory B-cell ALL would be alive and disease-free if they received obecabtagene autoleucel, with 49.5% alive and disease-free after 12 months.
Further, according to the investigators, the rates of immune-related adverse events were low: 2.4% of patients experienced severe cytokine-release syndrome, and 7.1% of patients experienced severe ICANS.
These data led to the recent FDA approval of obecabtagene autoleucel in the United States.
Claire Roddie, MD, PhD, lead investigator of the FELIX trial from UCL Cancer Institute and UCLH, said: “While we have a licensed CAR-T therapy to treat relapsed/refractory B-cell 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.… [O]ur results from the FELIX study demonstrate that [obecabtagene autoleucel] 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.”
Dr. Roddie is the corresponding author of The New England Journal of Medicine article.
Disclosure: The study was sponsored by Autolus Therapeutics. For full disclosures of the study authors, visit www.nejm.org.
