Gene-Edited CAR-T Delivers New Hope in Deadly T-Cell Leukemia: Research Shows
London: A novel gene-edited immunotherapy has demonstrated encouraging outcomes for children and adults with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL), a rare and highly aggressive blood cancer with limited treatment options.
The findings, published in the New England Journal of Medicine by Robert Chiesa of Great Ormond Street Hospital for Children NHS Trust, London, and colleagues, highlight the potential of universal base-edited CAR7 T cells to induce deep remission and enable curative stem-cell transplantation.
T-ALL arises from malignant T cells, making it particularly difficult to treat with conventional CAR-T therapies, which also rely on T cells. To overcome this challenge, researchers from Great Ormond Street Hospital (GOSH) and University College London (UCL) developed BE-CAR7, a next-generation CAR-T product created using base-editing technology. Unlike traditional gene editing, base editing allows precise DNA changes without cutting the DNA strand, reducing the risk of unwanted genetic damage.
The therapy was first administered in 2022 to a 13-year-old girl, Alyssa Tapley, after she failed to respond to chemotherapy and a bone marrow transplant and was considering palliative care. Her response marked a world first. Since then, eight additional children and two adults have received the treatment at GOSH and King’s College Hospital under a phase 1 trial and compassionate-use arrangements.
In the study, patients underwent lymphodepletion followed by infusion of BE-CAR7 cells derived from healthy donors sourced through the Anthony Nolan registry. The donor T cells were precisely edited to prevent rejection by the patient’s immune system, avoid self-destruction among the CAR-T cells, remain unaffected by other leukemia treatments, and selectively recognize and eliminate cancerous T cells expressing CD7.
Key findings were as follows:
- All 11 patients treated with BE-CAR7 T cells achieved complete morphologic remission by day 28.
- Very deep molecular remissions were observed in 82% of patients, enabling them to proceed to allogeneic hematopoietic stem-cell transplantation.
- At follow-up ranging from three months to three years, approximately 63–64% of patients remained disease-free, with the earliest treated patients now off therapy and in long-term follow-up.
- The trial met its primary safety objective, with the treatment considered acceptable for this high-risk patient population.
- Expected adverse events, including cytokine release syndrome, transient skin rashes, cytopenias, and infections, were reported but were generally manageable.
- The highest risk period was during immune suppression, particularly due to viral infections, before immune recovery following stem-cell transplantation.
BE-CAR7 cells were eliminated following stem-cell transplantation, enabling healthy donor-derived immune reconstitution. However, relapse with loss of the CD7 target antigen was documented in two patients, underscoring the need for continued refinement of the approach.
Developed through a long-standing research program led by Professor Waseem Qasim at UCL, with support from NIHR, Wellcome, the Medical Research Council, and GOSH Charity, BE-CAR7 represents a major step forward in cellular therapy. The results suggest that universal, base-edited CAR-T cells could offer a viable bridge to a cure for patients with otherwise untreatable T-ALL, opening new avenues for gene-edited cancer immunotherapy.
Reference:
DOI: 10.1056/NEJMoa2505478
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