01 June 2021

A small subset of T-cells could help treatment for children with leukaemia to be more effective, British researchers have reported.

Researchers at UCL and Great Ormond Street Hospital (GOSH), London, say they have found ‘stem cell memory T-cells’ are likely to be critical when destroying the cancer at the outset and for long-term immune surveillance.

Writing in Nature Cancer, they say their findings could improve the design and performance of CAR T-cell therapies.

Lead author Dr Luca Biasco, of UCL Great Ormond Street Institute of Child Health, said: “During clinical trials we have seen some very encouraging results in young patients with leukaemia; however it’s still not clear why CAR T-cells continue to be present in the long-term for some patients, stopping the cancer from returning, while others remain at a high risk of relapse.

“To ensure that a leukaemia treatment works any CAR T-cell therapy must have a prolonged effect on the way that the body recognises and removes cancer cells. In this study we tried to find the origin and nature of the T-cells that control these long-term responses.”

The team looked at the CAR T-cells of four patients involved in the CARPALL Phase I Study, which used CAT-19, a therapy developed to treat children with acute lymphoblastic leukaemia (ALL).

They compared CAR T-cells from two patients who still had CAR T-cells detectable in the blood more than two years after their treatment, with two who had lost their CAR T-cells in the one to two months post treatment.

Using a technique called ‘insertion site barcoding’, researchers studied what happened to the different types of CAR T-cells in patients over time.

Corresponding author Professor Persis Amrolia, of UCL Great Ormond Street Institute of Child Health and consultant in bone marrow transplant at GOSH, said: “Using this barcoding technique, we were able to see ‘stem cell memory T-cells’ play a central role both during the early anti-leukaemic response and in later immune surveillance, where the body recognises and destroys cancer cells.

“This suggests that this small sub-group of T-cells are critical to the long-term success of the therapy.”

The researchers believe doctors could measure the subtypes of CAR T-cells present in patients after treatment, to see if they will be able to preserve their CAR T-cells into the future, thereby avoiding relapse.

Professor Amrolia added: “This new insight may help us to improve our CAR T-cell therapy and work out which patients are at a higher risk of relapse and may benefit from a stem cell transplant after CAR T-cell therapy.”

Co-author Dr Martin Pule, who develops CAR T therapies at his lab at UCL Cancer Institute, said the research opens up new avenues to improve CAR design and manufacture.

The research received funding by Wellcome Trust and the National Institute for Health Research. All research at Great Ormond Street is supported by the NIHR GOSH Biomedical Research Centre.


Source:

Biasco L, Izotova N, Rivat C, Ghorashian S, Richardson R, Guvenel A, Hough R, Wynn R, Popova B, Lopes A, Pule M, Thrasher AJ & Amrolia PJ (2021) “Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients.” Nature Cancer, doi: 10.1038/s43018-021-00207-7

 

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