CRISPR-based genome editing has been used to make an 'off-the-shelf' cellular therapy for children with treatment-resistant leukaemia, marking an important step forward in the development of 'universal' genetically-altered treatments.
Researchers and clinicians from Great Ormond Street Hospital for Children (GOSH) in London and University College London's Great Ormond Street Institute of Child Health used viral gene transfer and CRISPR/Cas9 genome editing to add and delete genes respectively in donated T cells, a type of immune cell. This aimed to make the T cells able to detect and kill the patients' cancer cells, while not harming other tissues or themselves being rejected by the patients' own immune cells. These changes mean cells can be donated by healthy people in advanced and banked, which could hugely reduce the cost and delivery time for these complex treatments.
'This kind of unresponsive leukaemia is thankfully very rare, but we are pleased to be able to bring new therapies into play for some of the most difficult-to-treat childhood leukaemias, especially when all other options have been exhausted' said Professor Waseem Qasim, consultant immunologist at GOSH and lead author on the study. 'While there are challenges to overcome, this study is a promising demonstration of how emerging genome-editing technologies can be used to tackle unmet health needs in some of the sickest children we see'.
Publishing their results in Science Translational Medicine, modified cells from healthy donors were safely given to six children by London-based researchers in a phase I clinical trial to treat the blood cancer they had, known as B-cell acute lymphoblastic leukaemia.
All six children had already failed to respond to standard therapy, but within a month of infusion with the modified T cells the cancers of four of the patients went into remission. This allowed them to progress to receiving a stem cell transplant to rebuild their immune systems: two of those four remain in remission nine and 18 months later, while the cancer of the other two unfortunately returned.
This work builds on previous work from the group, in which similar modifications were made using TALENs, an older and more restrictive technology. In both trials, donor T cells were modified to produce a 'chimeric antigen receptor' (making 'CAR-T cells') allowing them to recognise and kill the cancer cells.
The group also deleted two genes from the T cells, CD52 and TRAC, which allows the modified cells to avoid the hazards that usually come with transplanting cells from one person to another.
These results come at a time when researchers around the world are trying to find the best combinations of genetic modifications to make CAR-T cells more effective (see BioNews 1131 and 1090).
As Dr Kanchan Rao, consultant at GOSH and co-author on the study put it: 'This study adds to the growing body of evidence that genome-edited T cells can be a viable alternative to currently available treatments. While this hasn't been successful in all cases, for some children in this study it has been life-saving'.
Sources and References
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Children at GOSH first to receive CRISPR-edited universal T-cells
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Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory B cell leukemia
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Pioneering gene editing technique can repair faulty T cells in patients with CTLA-4 insufficiency
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Scientists use CRISPR-Cas9 to repair white blood cell mutations
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