Health & Medicine, UK (Commonwealth Union) – Researchers, consisting of experts from University College London (UCL), have noticed new insights into the reason why certain children have a longer remission when contrasted with others following the receival of CAR T-cell therapy for leukaemia.
The recently published research project, featured in Nature Medicine, brought together clinical expertise and cutting-edge computational analysis to identify a genetic signature of CAR T-cells that exhibits long-term effectiveness.
CAR T-cells are T-cells that have been genetically modified to specifically target leukemia, particularly B-cell acute lymphoblastic leukemia (B ALL), which is a rare and difficult-to-treat form of blood cancer. Over the years, CAR T-cell therapy has emerged as a well-established treatment option for children with relapsed or incurable B ALL.
A viral vector infects the T cells, causing them to express the receptor on their surface. These modified CAR T cells are then expanded in the laboratory to generate a large population of cells before being infused back into the patient. Once inside the patient’s body, CAR T cells recognize the specific antigen expressed on cancer cells, leading to their activation and subsequent destruction of the cancer cells.
A crucial factor in determining the success of the treatment, leading to a sustained remission of leukemia and enabling children to live cancer-free lives, is the durability of CAR T-cells within the body.
A limited knowledge existed till the present, regarding the factors that contribute to the longevity of these cells. Consequently, it was unclear whether the treatment could deliver long-term efficacy without the need for additional therapies.
A joint effort involving the research team consisting of experts from UCL Great Ormond Street Institute of Child Health (UCL GOS ICH), Great Ormond Street Hospital (GOSH), and the Wellcome Sanger Institute undertook a long-term study called CARPALL, involving families who had undergone CAR T-cell treatment known as AUTO1. The objective was to gain insights into why certain CAR T-cells exhibit long-lasting presence within the body.
This research represents an initial milestone in unraveling the factors behind the persistence of CAR T-cells. The team intends to expand upon the identified genetic signature to pinpoint crucial markers within cell populations. Ultimately, their aim is to comprehend whether it is possible to identify or even engineer CAR T-cells that can endure over the long term even before the commencement of treatment.
Co-senior author, Dr Sara Ghorashian of the UCL Great Ormond Street Institute of Child Health and GOSH says “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.”
The research team had the opportunity to examine cells from ten children who participated in the CARPALL trial for a duration of up to five years after receiving their initial CAR T-cell therapy. This extensive study has yielded fresh insights into the factors influencing the persistence of CAR T-cells in a patient’s bloodstream. Understanding why some of these cells remain while others disappear early is crucial, as the premature loss of CAR T-cells can potentially lead to cancer recurrence.
The application of advanced techniques that analyze individual cells at a genetic level, the scientists successfully identified a distinctive “signature” present in CAR T-cells that exhibit long-lasting presence. This signature implies that these durable CAR T-cells undergo a transformative process within the bloodstream, enabling them to effectively patrol the patient’s body for cancer cells and continue their vigilant surveillance.
