Scientists at University College London and Great Ormond Street Hospital have developed a base-edited therapy called BE-CAR7 that uses universal CAR T-cells to treat relapsed or refractory T-cell acute lymphoblastic leukemia. Early trial results published in the New England Journal of Medicine and presented at the American Society of Hematology Annual Meeting indicate deep remissions in most patients, including those who did not respond to standard treatments, by tackling long-standing challenges in T-cell–based therapies.
In 2022, researchers at University College London (UCL) and Great Ormond Street Hospital (GOSH) delivered what they describe as the world’s first treatment made using base editing to a 13-year-old girl from Leicester, Alyssa, who had T-cell acute lymphoblastic leukemia (T-ALL).
According to UCL and GOSH, Alyssa was diagnosed in May 2021 after repeated viral illnesses and fatigue, and her leukemia did not respond to chemotherapy or to an initial bone marrow (stem cell) transplant.
She was offered an experimental therapy known as BE-CAR7, which uses base-edited immune cells. Reports from UCL and subsequent media coverage say the treatment cleared her leukemia. Now 16, she is described as leading a normal teenage life, including activities such as sailing and working toward her Duke of Edinburgh’s Award, and she has spoken of wanting to become a research scientist.
Since Alyssa’s treatment, the BE-CAR7 therapy has been administered to a further eight children at GOSH and two adults at King’s College Hospital in London, bringing the total treated in this programme to 11 patients.
BE-CAR7 employs base editing, an advanced version of CRISPR technology that can precisely change single DNA letters without cutting both strands of the genome. Researchers say this approach reduces the risk of certain types of DNA damage that can occur with conventional CRISPR editing.
In the BE-CAR7 process, healthy donor T-cells are engineered into so-called universal CAR T-cells. The team uses base editing to inactivate the genes encoding the T-cell receptor (to reduce the risk of graft-versus-host disease) and the CD7 and CD52 markers. This is designed to prevent the engineered cells from attacking each other, to allow them to evade depletion by lymphodepleting antibodies, and to help them avoid immune rejection. A chimeric antigen receptor (CAR) that targets CD7, a protein commonly expressed on T-ALL cells, is then introduced so the modified cells can seek out and destroy leukemia cells.
Updated clinical trial results from this first-in-human study have been published in the New England Journal of Medicine and presented at the 67th American Society of Hematology Annual Meeting. In the phase 1 trial, BE-CAR7 T-cells were given to nine children and two adults with relapsed or refractory T-ALL after lymphodepleting chemotherapy.
Researchers report that all 11 patients achieved complete morphologic remission with incomplete count recovery by day 28 following BE-CAR7 infusion. Nine patients (82%) achieved very deep remissions, as measured by highly sensitive tests such as flow cytometry or polymerase chain reaction, which enabled them to proceed to allogeneic stem cell transplantation without detectable disease. The remaining two patients, who still had measurable residual leukemia, did not proceed to transplant and received palliative care.
Follow-up reported in the New England Journal of Medicine shows that seven of the 11 patients (64%) remain in ongoing remission between three and 36 months after transplantation. The first patients treated have now been off therapy and leukemia-free for around three years. The trial authors caution that longer follow-up and larger studies will be needed to confirm how durable these responses will be.
The treatment was associated with anticipated side effects. Complications included low blood counts, cytokine release syndrome ranging from mild to severe, transient rashes and opportunistic infections, particularly viral infections during the period when the immune system was rebuilding after transplant. Investigators describe these toxicities as in line with expectations for intensive cellular immunotherapy and subsequent transplantation, though they note that viral reactivations were frequent and three patients had significant virus-related complications.
Professor Waseem Qasim of UCL, who led the research, said in a statement that the study shows universal or “off the shelf” base-edited CAR T-cells can be used to target very resistant cases of CD7-positive leukemia. Dr. Rob Chiesa, a consultant in bone marrow transplantation at GOSH and lead author of the New England Journal of Medicine paper, has noted that about 20% of children with T-cell leukemia may not respond adequately to standard treatments or may relapse, and that this approach offers a new option for some of those high-risk patients. Dr. Deborah Yallop, a hematologist at King’s College Hospital, has said clinicians there have seen impressive responses in adults with T-ALL whose disease had appeared incurable.
The study is sponsored by Great Ormond Street Hospital and funded by the UK Medical Research Council, Wellcome and the National Institute for Health and Care Research. According to UCL, further expansion of the trial to additional patients is planned, supported in part by a £2 million investment from GOSH Charity. Manufacturing of the BE-CAR7 cells takes place at the Zayed Centre for Research into Rare Disease in Children at the UCL Great Ormond Street Institute of Child Health.
Researchers and clinicians involved in the trial stress that BE-CAR7 remains an experimental therapy, currently available only within clinical studies or compassionate-use arrangements. Nonetheless, the early results suggest that universal base-edited CAR T-cells may offer a powerful new strategy for patients with aggressive T-ALL who have exhausted existing options.
