A genetic signature of CAR T-cells has been identified that could explain why some children have a longer remission than others after receiving the therapy for leukaemia.
Researchers at University College London, Great Ormond Street Hospital and the Wellcome Sanger Institute combined novel immune therapy design and computational analysis to identify a genetic signature of CAR T-cells that could be the most effective in the long term.
CAR T-cells are now an established treatment option for children with a relapsed or incurable B-cell acute lymphoblastic leukaemia (B-ALL).
One of the key factors that determines if the treatment will lead to a long-lasting remission of the leukaemia is how long the CAR T-cells last in the body.
The research team worked with families for years after their CAR T-cell treatment (called AUTO1) as part of the CARPALL study, to begin to build a picture of why some CAR T-cells stay in the body long-term.
The study, published in Nature Medicine, provides the first stepping-stone in understanding why some CAR T-cells persist, the researchers say.
They now aim to build on the newly discovered signature to identify key markers in cell populations and establish if there is a way to spot CAR T-cells that will persist long-term, or even create them before treatment begins.
Lead author Dr Nathaniel Anderson said: “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.
“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.”
The team studied cells from 10 children who were enrolled in the CARPALL trial, for up to five years after their original CAR T-cell treatment.
Identifying the unique signature in long-lasting CAR T-cells suggested these cells transform into a different state that enables them to continue looking for cancer cells. This signature was seen across thousands of cells within patients, and between patients, as well as in adults treated with a different CAR T-cell product for a different type of leukaemia.
Co-senior author Dr Sara Ghorashian said: “This data for the first time shows us the characteristics of long-lasting CAR T-cells which are responsible not just for curing children with ALL in our study but also seen in adults treated with a different CAR T-cell product for a different type of leukaemia. As such, this provides us with confidence that the signature may unlock mechanisms of CAR T-cell persistence more generally and allow us to develop better treatments.”
Anderson ND, Birch J, Accogli T, Criado I, Khabirova E, Parks C, Wood Y, Young MD, Porter T, Richardson R, Albon SJ, Popova B, Lopes A, Wynn R, Hough R, Gohil SH, Pule M, Amrolia PJ, Behjati S, Ghorashian S. (2023) “Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia.” Nature Medicine, doi: 10.1038/s41591-023-02415-3.
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