Gene editing saves Layla from leukaemia

In an impressive demonstration of the power of gene editing, designer immune cells have been successfully used to treat an infant cancer patient.

The milestone marks the first time TALENs (transcription activator-like effector nucleases) gene-editing technology has been used in a human patient with leukaemia. The data was presented to the 57th American Society of Hematology (ASH) Annual Meeting in December last year.

The patient at the centre of the story, Layla Richards, was diagnosed with an aggressive form of infant acute lymphoblastic leukaemia (ALL) at just 14 weeks of age. Despite several rounds of chemotherapy and a bone marrow transplant at London’s Great Ormond Street Hospital (GOSH), her cancer returned shortly before her first birthday. Further chemotherapy was no longer viable, and it reached the stage where her doctors were suggesting palliative care.

At this point, Layla’s parents were informed that an experimental treatment, which had only been trialled in mice, was being developed by GOSH in conjunction with the University College London (UCL) Institute of Child Health (ICH) and biopharma company Cellectis. The team, led by Professor Waseem Qasim from UCL ICH, was working on an immunotherapy candidate called UCART19, which works by making additions to healthy T-cells.

UCART19 employs TALENs as molecular scissors, used to edit parts of target genes, while chimeric antigen receptors (CARs) are added to the surface of the T-cells. These changes cause the T-cells to behave in two specific ways: they become invisible to a powerful leukaemia drug that would usually kill them and they are reprogrammed to only target and fight against leukaemia cells.

“Previous CAR-based therapies have utilised a patient’s own cells, which means treatments have to be individually manufactured,” explained Dr Mark Osborn, from the University of Minnesota. In the case of UCART19, however, donor T-cells are used instead.

“This ‘off the shelf’ approach allows for the generation and banking of a population of cells that can be delivered to any patient for widespread and urgent use,” noted Dr Osborn. This was particularly important in Layla’s case, as she did not have enough of her own healthy T-cells for collection and modification.

The catch was that only one vial of the treatment was available — and it had not yet been through final-stage testing or clinical trials. It took an emergency ethics meeting, and special approval from Cellectis, to give Layla the chance she needed.

The treatment consisted of 1 mL of genetically engineered UCART19 cells, delivered to Layla via an intravenous line. The process took around 10 minutes and no significant toxicity was exhibited. Some weeks afterwards, Layla developed a mild rash. Her immune system was recognising the treatment. It was working.

“As this was the first time that the treatment had been used, we didn’t know if or when it would work, and so we were over the moon when it did,” said Layla’s lead clinician, Professor Paul Veys. “Her leukaemia was so aggressive that such a response is almost a miracle.”

Once doctors were confident that all the leukaemia cells had been removed, Layla was given a bone marrow transplant to replace her blood and immune system, which had been wiped out. She is now recovering at home, although she returns to GOSH regularly to check that her bone marrow cells are healthy and her blood counts are continuing to normalise.

“Even though she is well at the moment, we still don’t know what the future holds,” admitted Layla’s father, Ashleigh. “She will still have monthly bone marrow checks for now and might be on some medicines for the rest of her life.”

Layla’s story has made international headlines, with scientists around the world recognising the potential of the gene-editing technology. Professor Peter Koopman, from The University of Queensland’s Institute for Molecular Bioscience, noted that blood diseases are especially suitable for the technology as “the relevant cells can be readily obtained from the patient, are already separated (as opposed to being relatively inaccessible in a solid organ), can be modified and amplified, and [can be] replaced where they need to be”.

“A particularly clever aspect of the way this treatment was designed is that some time later, the engineered cells can themselves be removed from the body, virtually eliminating the already small risk that those cells themselves may cause adverse effects,” he added.

Dr Stephan Grupp, from the University of Pennsylvania Perelman School of Medicine, was particularly impressed with the use of donor cells as opposed to those of the patient. He was supported by UCL’s Dr Simon Waddington, who said an off-the-shelf method could reduce the cost and complexity of treatment.

However, Dr Grupp maintained some scepticism about the effectiveness of the technology. He noted that “the patient had a high leukaemia burden after failing a newer leukaemia treatment called blinatumomab, but then got two rounds of standard chemotherapy and the amount of leukaemia dropped to a very low level. This means at the time of receiving the T-cells, the patient was technically already in remission.”

Dr Grupp and other scientists suggested that larger clinical trials with more patients, who are not responding to chemotherapy at the time, will be required in order to establish long-term safety and efficacy, potential side effects and applicability to the wider population. Fortunately, that is what Cellectis aims to do, with early-phase clinical trials planned for large patients groups this year.

“We expect to accelerate our clinical development of TALEN gene-edited allogeneic CAR-T therapies to further confirm this encouraging clinical proof of concept,” said Dr Mathieu Simon, executive vice president and chief operating officer at Cellectis.

Furthermore, Professor Qasim himself has acknowledged that the treatment is not yet ready for use among the general patient population. “We have only used this treatment on one very strong little girl,” he said, “and we have to be cautious about claiming that this will be a suitable treatment option for all children.

“But this is a landmark in the use of new gene engineering technology, and… it could represent a huge step forward in treating leukaemia and other cancers.”

Image caption: Professor Waseem Qasim, who developed and carried out the gene therapy.