Immature blood cells in leukemia.
Immature blood cells in leukemia. [toeytoey2530/Getty Images]

New findings may explain why some children with leukemia have a longer remission than others after having CAR T-cell therapy. Researchers at University College London (UCL), Great Ormond Street Hospital, and the Wellcome Sanger Institute identified a unique signature in chimeric antigen receptor (CAR) T-cells that are long lasting—a key factor in how well the therapy works.

They used high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples. The study was published today in Nature Medicine.

“Through cutting-edge single cell genomics, we have, for the first time, been able to crack the code of persistence in CAR T-cells in children with great clarity,” said Nathaniel Anderson, lead author and a fellow at the Wellcome Sanger Institute, said.

The team hopes their findings will help clinical teams better determine who will best respond to CAR T-cell treatment and enable manufacturers of these products to optimize them.

In recent years, CAR T-cells—genetically engineered T-cells—have become an established treatment option for children with a relapsed or incurable rare form leukemia (B-cell acute lymphoblastic or B ALL).

One of the key factors that determines whether the treatment will lead to a long-lasting remission of the leukemia is how long the CAR T-cells last in the body. Until now, little has been known about this, making it impossible to know if the treatment is likely to work long-term without further therapy.

This team combined expertise in immune therapy design and computational analysis to identify a genetic signature of CAR T-cells that will last. They worked with families for years after the patient’s CAR T-cell treatment (called AUTO1,) as part of the study.

The study looked at cells from 10 children for up to five years after their original CAR T-cell treatment using single-cell gene expression and T cell receptor sequencing. The team were able to identify a unique signature in long-lasting CAR T-cells. Their work also suggests such cells transform into a different state, and that is why they continue attacking cancer cells.

This signature was seen across cells and patients as well as in adults treated with a different CAR T-cell product for a different type of leukemia. But it was not identified in other types of immune cells. This finding, the authors say, suggested that the signature may not only be a marker of these long-lasting cells but could actually be what makes them persist in the body and allows for a longer remission in children.

As part of the study, the researchers identified the key genes in CAR T-cells that appeared to enable them to persist. These genes, they say, provide a starting point for future studies to identify markers of persistence in CAR T-cell.

The team now aim to build on the signature discovered in this project to identify key markers in cell populations and understand if there is a way to spot, or even create, CAR T-cells that will persist long-term before treatment begins.

“We hope that our research will provide the first clue as to why some CAR T-cells last for a long time—which we know is vital for keeping children cancer-free after treatment. Ultimately, this work will help us to continue to improve this already life-changing treatment,” Anderson said.

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