New gene-editing technology could treat children with drug-resistant leukemia

Researchers from UCL and Great Ormond Street Hospital for Children (GOSH) have developed donor T cells to try to treat critically ill children with drug-resistant leukemia who would otherwise have exhausted all available therapies.

The Phase I study, published in Science Translational Medicine, is the first human application of “universal” CRISPR-edited cells and represents a significant advance in the use of gene-edited cells to treat cancer.

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 cuts the cells’ DNA and inserts a new genetic code. In this case, the genetic code enables the T cells to express a receptor – called a chimeric antigen receptor (CAR) – that can recognize a marker on the surface of cancerous B cells and then destroy them.

The T cells were then further genetically edited so that they could be used ‘off the shelf’ without the need for donor matching.

Lead author Professor Qasim said: “Fortunately, this type of unresponsive leukemia is very rare, but we are excited 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.”

“While there are challenges to be overcome, this study is an promising demonstration of how emerging genome-editing technologies can be used to address unmet health needs in some of the sickest children we see.”

The study builds on earlier work by Professor Qasim’s team, which used older technologies.

2015, a year-old patient using CAR-T cell therapy to rid her body of leukemia. Here, white blood cells were collected from a healthy donor and processed in a special lab using “molecular scissors” called TALENS (a precursor to CRISPR) to make the cells suitable for transplantation into all patients and capable of preventing leukemia to hunt down and eliminate the body.

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

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

As a result, scientists are now exploring genome editing so that donated cells can be pre-engineered and used in multiple patients to reduce costs and make treatments more accessible.

The researchers made their donor CAR T-cell banks using a single deactivated virus to deliver both the CAR and a CRISPR guidance system, and then applied mRNA technology – a molecule that carries the instructions , which instruct the cells to make a protein – to activate the gene editing steps.

The donors were all healthy UK volunteers and were provided by the Anthony Nolan Registry.

The process

The study enrolled six children aged 14 months to 11 years with relapsed and treatment-resistant B-cell acute lymphocytic leukemia (B-ALL). They received therapy through February 2022.

All of the children had previously been on standard UK treatments for B-ALL, but had seen their disease come back on several occasions.

The patients were given the processed cells by intravenous infusion and the treatment was expected to be active for about four weeks. It is hoped this is enough time to achieve deep remission, a state where her cancer has dramatically reduced or become undetectable. If successful, patients could then receive a bone marrow stem cell transplant to help restore a healthy immune system.

Four of the first six children treated went into remission within 28 days, allowing them to receive a stem cell transplant. Of these four children, two children remain in sustained remission 9 months and 18 months respectively after treatment, while unfortunately two relapsed after their stem cell transplant.

In this study, overall side effects were within expectations and were treated in hospital, with one patient requiring a short ICU period.

dr Kanchan Rao, Bone Marrow Transplant Advisor at GOSH said, “This study adds to the growing evidence that genome-edited T cells may be a viable alternative to currently available treatments. While this was not successful in all cases, it was life-saving for some of the children in this study.”

The study showed that the engineered T cells could eradicate otherwise incurable leukemia in some patients, but side effects and challenges remained.

The next step is for the researchers to offer the treatment to more children earlier in their treatment pathway, when their cancers are not as advanced.

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

/Public release. This material from the original organization/author(s) may be post-date in nature and may be edited for clarity, style and length. The views and opinions expressed are those of the author(s).

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