The researchers, who published their findings in Nature Medicine, utilized clinical expertise and state-of-the-art computational analysis to identify a genetic signature of CAR T-cells that will offer the highest long-term effectiveness.

CAR T-cells, which are T-cells genetically engineered to target leukemia, have emerged as a well-established treatment option for children diagnosed with B-cell acute lymphoblastic leukemia (B ALL), a rare and incurable form of blood cancer, that has relapsed or is deemed untreatable.

The duration of CAR T-cell persistence in the body is a critical determinant for achieving a sustained leukemia-free state, enabling children to live without cancer. However, little was previously understood regarding the factors influencing the longevity of these cells and their potential to provide long-term efficacy, eliminating the need for additional therapy.

The UCL Great Ormond Street Institute of Child Health (UCL GOS ICH), Great Ormond Street Hospital (GOSH), and the Wellcome Sanger Institute formed a collaborative research team. They actively engaged with families over several years following their AUTO1 CAR T-cell treatment as part of the CARPALL study. Their goal was to uncover the factors contributing to the long-term presence of CAR T-cells within the body.

This research marks the initial milestone in comprehending the persistence of specific CAR T-cells. The team intends to expand upon the identified genetic signature, aiming to pinpoint crucial markers within cell populations. Ultimately, they aim to determine if there is a possibility to identify or even engineer CAR T-cells that exhibit long-term persistence prior to initiating treatment.

Co-senior author, Dr Sara Ghorashian (UCL Great Ormond Street Institute of Child Health and GOSH) 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.

We are indebted to all of the children and families who make research like ours possible – it is only through their dedication that we are able to build our understanding of these new therapies and build better treatments for children across the world.”

Dr. Nathaniel Anderson, the lead author from the Wellcome Sanger Institute, expressed-

"Using state-of-the-art single-cell genomics, we have successfully deciphered the mechanisms behind the persistence of CAR T-cells in children with unprecedented 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 research team actively examined cells from 10 children participating in the CARPALL trial, studying them for up to five years after their initial CAR T-cell treatment. This investigation yielded a fresh comprehension of why certain CAR T-cells endure within a patient's bloodstream, while others dissipate prematurely, potentially leading to cancer recurrence.

Employing genetic-level analysis techniques to scrutinize individual cells, the scientists successfully identified a distinctive "signature" present in long-lasting CAR T-cells. The signature indicated that these enduring CAR T-cells undergo a transformative state within the bloodstream, enabling them to persistently surveil the patient's body for cancer cells.

Significantly, this signature manifested consistently across various cells and patients, including adults treated with a different CAR T-cell product for a distinct form of leukemia. Conversely, it remained absent in other types of immune cells. This observation implies that the identified signature not only serves as a marker for these enduring cells but may also play a vital role in their longevity within the body, facilitating extended remissions in children.

In the study, the researchers actively identified the crucial genes within CAR T-cells that seemingly endowed them with the ability to endure within the body over an extended period. These genes play a pivotal role as they offer a foundation for subsequent investigations to pinpoint markers of persistence in CAR T-cell products during their production, ultimately leading to enhanced effectiveness.

Dr Sam Behjati, co-senior author, Group Lead (Wellcome Sanger Institute and Addenbrooke’s Hospital, Cambridge) said-

“This study is a fantastic step forward in our understanding of CAR T-cell persistence and illustrates the power of collaborative science and combining pioneering clinical research with cutting-edge genomic science. It is crucial that we continue to develop and build on these new treatments to help more children with leukaemia across the world.”