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Researchers say 'stem cell memory T-cells' appear critical in both destroying the cancer at the outset and for long term immune surveillance and exploiting this quality could improve the design and performance of CAR T therapies.

Explaining the study, published inÌýNature Cancer, lead author Dr Luca Biasco (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."

In CAR T therapy, immune cells (T-cells) are genetically engineered to contain a molecule called a chimeric antigen receptor (CAR) on their surface which can specifically recognise cancerous cells.

Researchers assessed the CAR T-cells of patients involved in the CARPALL Phase I Study, which used a new CAR molecule known as CAT-19 developed between UCL Cancer Institute and UCL Great Ormond Street Institute of Child Health, for treatment in children with acute lymphoblastic leukaemia (ALL).

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

Using a technique called 'insertion site barcoding', researchers were able to study the fate of different types of CAR T-cells in patients after they were given.

Corresponding author Professor Persis Amrolia, based at »Ê¼Ò»ªÈË 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."

Researchers say, this work indicates that the teams caring for patients could measure the types of CAR T-cells present after some someone has had their anti-leukaemia therapy, to gain an indication of whether they will be able to preserve their CAR T-cells into the future, 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."

Dr Biasco added: "It was extremely rewarding to see how the application of our new barcoding technology to study CAR T-cells is unveiling such important information about what happens to these cells after they are given to patients. We now plan to expand the technology we established at »Ê¼Ò»ªÈË and validate these findings in larger groups of patients."

Co-author Dr Martin Pule, who develops CAR T therapies at his lab at »Ê¼Ò»ªÈË Cancer Institute, said: "This research opens up new avenues to improve CAR design and manufacture, improving the performance of CAR T-cell therapy, to achieve a combination of early tumour clearance and long-term protection from relapses in patients with B cell leukaemia."

Links

• UCL Great Ormond Street Institute of Child Health
• Infection, Immunity and Inflammation Research and Teaching Department at the UCL Great Ormond Street Institute of Child Health
• UCL Cancer InstituteÌý

Image

• Killer T cells surround a cancer cell, Credit: Alex Ritter, Jennifer Lippincott Schwartz and Gillian Griffiths,ÌýÌý(CC BY 2.0)

Media contact

Rowan Walker

Tel: +44 (0)20 3108 8515

Email: rowan.walker [at] ucl.ac.uk