Researchers are using CRISPR-edited T cells to treat critically ill children with drug-resistant leukemia

Researchers are using CRISPR-edited T cells to treat critically ill children with drug-resistant leukemia

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 develop donor T cells to try to treat critically ill children with resistant leukemia who have otherwise exhausted all available therapies.

This Phase I study, published in Science Translational Medicine, is the first application of "universal" CRISPR-edited cells in humans and represents a significant advance in the use of gene-edited cells for cancer treatment. As part of the study, the research team built and applied a new generation of "universal" genome-edited T cells, building on previous work in which older, less accurate technologies were used.

T cells have been modified with CRISPR, which makes a cut into the cells' DNA and inserts genetic code. In this case, this part of the genetic code allows 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 gene-edited using CRISPR so that they could be used “off the shelf” without the need for donor matching.

While a number of CAR T-cell therapies are now offered on the NHS, they rely on collecting and generating a patient's own cells. This is expensive and not always feasible or possible in a short period of time. Genome editing is being studied so that donated cells can be premade and used in multiple patients to reduce costs and make treatments more accessible.

In specialized cleanrooms at GOSH, researchers created their donor CAR T cell banks using a single deactivated virus to deliver both the CAR and a CRISPR guidance system, then applied cutting-edge mRNA technology to activate the gene editing steps. The donors were all healthy volunteers from the UK and were provided by the Anthony Nolan Registry.

The process

Six children aged 14 months to 11 years with relapsed and treatment-resistant B-ALL were treated through February 2022. All of the children had previously undergone standard British treatments for B-ALL, but unfortunately saw their disease recur on several occasions.

Patients were infused with the edited cells, which were expected to be active for about four weeks. This is long enough to hopefully achieve deep remission, a state in which their cancer is dramatically reduced or no longer detectable. If successful, patients could then undergo a bone marrow stem cell transplant to restore a healthy immune system.

Four of the first six children treated entered 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 after treatment, respectively, while unfortunately two suffered a relapse after their stem cell transplant.

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

Professor Waseem Qasim, Consultant Immunologist at GOSH and Professor of Cell and Gene Therapy at UCL GOS ICH lead author, said:

“This type of unresponsive leukemia is fortunately very rare, but we are excited to bring new therapies to the table for some of the most difficult-to-treat childhood leukemias, particularly when all other options have been exhausted.

“Although there are challenges to overcome, this study is a 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 children treated in this study had the worst possible prognosis for their disease. It is only through clinical trials that we can save more young lives, and we are forever grateful to all the families involved in this trial, which will help more children in the future.”

Professor Ajay Vora, Consultant Hematologist and Leukemia Specialist at GOSH

Dr. Kanchan Rao, bone marrow transplant consultant at GOSH, said:

"This study adds to the growing evidence that genome-edited T cells may be a viable alternative to currently available treatments. Although not successful in all cases, it was life-saving for some children in this study."

The next step is for 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.

This research was funded by the National Institute of Health and Care Research, the NIHR GOSH Biomedical Research Center and the Medical Research Council. The research team would like to thank Anthony Nolan for providing the donor T cells and all donors who donate to the registry.

Source:

University College London

Reference:

Ottaviano, G., et al. (2022) Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for the treatment of children with refractory B-cell leukemia. Science Translational Medicine. doi.org/10.1126/scitranslmed.abq3010.

.