Researchers at Great Ormond Street Hospital for Children (GOSH) and UCL Great Ormond Street Institute of Child Health (UCL GOS ICH) have used CRISPR/Cas9 technology to engineer donor T cells to try to treat seriously ill children with resistant leukemia, who had otherwise exhausted all available therapies.
This Phase I trial, published in Science Translational Medicine, is the first use of ‘universal’ CRISPR-edited cells in humans and represents a significant step forward in the use of gene-edited cells for cancer treatment. As part of the trial the research team, built and applied a new generation of ‘universal’ genome-edited T cells, which builds on previous work1 that had used older, less accurate technology.
T cells were modified using CRISPR which makes a cut in the cells’ DNA and insert a genetic code. In this case this piece of genetic code allows the T cells to express a receptor — called a chimeric antigen reception (CAR) — that can recognise a marker on the surface of cancerous B cells and then destroy them. The T cells were then gene edited using CRISPR so that they could be used ‘off the shelf’ without any donor matching needed.
While a number of CAR T-cell therapies are now being provided by the NHS, they rely on collecting and engineering a patient’s own cells. This is expensive and is not always feasible or possible in a short period of time. Genome editing is being investigated to allow donated cells to be pre-manufactured and used in multiple patients, aiming to reduce costs and make the treatments more accessible.
In specialist clean rooms at GOSH, researchers manufactured their banks of donor CAR T-cells using a single disabled virus to transfer both the CAR and a CRISPR guidance system, and then applied cutting-edge mRNA technology to activate the gene editing steps. Donors were all healthy volunteers from the UK and provided by the Anthony Nolan Registry.
The trial
Six children aged 14 months to 11 years with relapsed and treatment-resistant B-ALL have been treated up to February 2022. All of the children had previously been through standard UK treatments for B-ALL but had sadly seen their disease return multiple times.
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