UCL: New gene editing technology could treat children with resistant leukaemia

The 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.

The researchers, led by Professor Waseem Qasim (UCL Great Ormond Street Institute of Child Health & Consultant Immunologist at GOSH) used a technique known as CRISPR/Cas9, which makes a cut in the cells’ DNA and inserts a new genetic code. In this case, the 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 further so that they could be used “of the shelf” without any donor matching needed.

Lead author, Professor Qasim, said: “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.

“Whilst 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.”

The study builds on previous work from Professor Qasim’s team that used older technology.

In 2015 a one-year-old patient with the CAR T-cell therapy to clear her body of leukaemia. Here, white blood cells were collected from a healthy donor and engineered in a special laboratory using “molecular scissors” called TALENS (a precursor to CRISPR), to make the cells suitable for transplant into any patients and capable of hunting down and clearing leukaemia across the body.

Following the success of this experimental treatment, larger studies reported on 21 patients – both adults and children – that were treated.

While several CAR T-cell therapies are now being provided by the NHS, they rely on collecting and engineering a patient’s own cells. This can be expensive and not always possible in a short period of time.

As a result, scientists are now investigating genome editing to allow donated cells to be pre-manufactured and used in multiple patients, aiming to reduce costs and make the treatments more accessible.

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 mRNA technology – a molecule that contains the instructions that direct the cells to make a protein – to activate the gene editing steps.

Donors were all healthy volunteers from the UK and provided by the Anthony Nolan Registry.

The trial

The trial involved six children aged 14 months to 11 years, with relapsed and treatment-resistant B-Cell Acute Lymphblastic Leukaemia (B-ALL). They were given the therapy up to February 2022.

All of the children had previously been through standard UK treatments for B-ALL but had seen their disease return multiple times.

Patients were given the edited cells through an intravenous infusion and the treatment was expected to be active for around four weeks. It is hoped that this is enough time to achieve deep remission, a state where their cancer is dramatically reuced or undetectable. When successful, patients were then eligible to have a bone marrow stem cell transplant to help re-establish a healthy immune system.

Four of the first six children treated entered remission within 28 days, which allowed them to receive a stem cell transplant. Of those four children, two children remain in ongoing remission 9 months and 18 months after treatment respectively, while sadly two relapsed following their stem cell transplant.

In this study, overall side effects were within expectations and were managed in hospital, with one patient requiring a short period of intensive care.

Dr Kanchan Rao, Consultant in Bone Marrow Transplant at GOSH, said: “This study adds to the growing body of evidence that genome edited T cells can be a viable alternative to currently available treatments. Whilst this hasn’t been successful in all cases, for some children in this study it has been life-saving.”

The trial showed that the edited T-cells could clear the otherwise-incurable leukaemia in some patients, but that side effects and challenges remained.

The next step is for researchers to offer the treatment to more children, earlier in their treatment pathways when their cancers have not progressed so far.

Professor Qasim’s team are based at the Zayed Centre for Research into Rare Disease in Childhood, a partnership between UCL GOS ICH and GOSH.