Unlocking the mystery of long-lasting cancer treatment

In recent years, CAR T-cells, genetically engineered T-cells (a type of immune cell), designed to target leukaemia, have become an established treatment option for children with a relapsed or incurable rare form leukaemia (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 leukaemia – allowing children to live cancer free – is how long the CAR T-cells last in the body. Until now, little has been known about what makes these cells last in the body and, therefore, whether the treatment is likely to work long-term without further therapy.

A collaborative research team from across Great Ormond Street Hospital (GOSH), the Wellcome Sanger Institute and the UCL Great Ormond Street Institute of Child Health (UCL GOS ICH) 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.

This work provides the first stepping-stone in understanding why some CAR T-cells persist. The team aims to build on the signature discovered in this project to identify key markers in cell populations and ultimately understand if there is a way to spot, or even create CAR T-cells that will persist long-term before treatment begins.

The hope is that this knowledge will eventually enable clinical teams delivering CAR T-cell therapies to better understand which patients will best respond to treatments and enable manufacturers to optimise their methods to support persistence – leading to better outcomes for patients.

The team were able to study cells from 10 children who were enrolled in a pioneering clinical trial (CARPALL trial), for up to 5-years after their original CAR T-cell treatment. This has provided them with a new understanding as to why some of these CAR T-cells stay around in a patient’s bloodstream, and why others vanish early – which can in some cases allow the cancer to return.

Using techniques that analyse individual cells at a genetic level to understand what they do; the scientists were able to identify a unique “signature” in long-lasting CAR T-cells. The signature suggested that long-lasting CAR T-cells in the blood transform into a different state that enables them to continue policing the patient’s body for cancer cells.

Vitally, 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 leukaemia. But it was not identified in other types of immune cells. This suggested that the signature the authors identified 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 in the body for a long time. Importantly these genes will provide a starting point for future studies to identify markers of persistence in CAR T-cell products as they are made and ultimately improve their effectiveness.

Studies such as this are only possible because of the dedication of the children and families who take part in research. For scientists to investigate the long-term persistence of cells, children had to continue to donate cells to the study for up to 5-years after their initial treatment.

Austin was diagnosed with B ALL at the age of two, by the age of eight he’d been through three relapses and extensive treatment including two bone marrow transplants. By the time of his fourth relapse, he had exhausted all conventional therapy options. In October 2016, Austin received an infusion of CAR T-cells as part of the CARPALL clinical trial.

Over 6 years later and Austin, now 14, is still cancer free, with long-lasting CAR T-cells detectable in his blood. He is just one of 10 children who have been donating samples to this study since their infusions.

This continued commitment to studies is helping researchers to better understand new, cutting-edge therapies and improve them for future families.

This research was supported by a CRUK/AIRC Accelerator Award Scheme for the INCAR consortium. Wellcome provided institutional and personal (SB) funding support. Marie Sklodowska-Curie Actions supported NA. The Olivia Hodson Cancer Fund also supported this work.

The original CARPALL study was funded by Children with Cancer, GOSH Charity and JP Moulton Trust. Support was also provided by the National Institute for Health and Care Research Biomedical Research Centres at Great Ormond Street Hospital for Children NHS Foundation Trust, University College London Hospital, King’s Health Partners, Great Ormond Street Hospital and University College London Hospital.