Mystery Behind Long Lasting Cancer Treatment Revealed

Researchers at UCL, Great Ormond Street Hospital, and the Wellcome Sanger Institute have given new insights into why some children have a longer remission than others after receiving cutting-edge CAR T-cell therapy for cancer treatment.

The interdisciplinary research initiative, which was published today in Nature Medicine, combines expertise in innovative immune therapy design with cutting-edge computational analysis to find a genetic profile of CAR T-cells that will be most effective in the long run.

CAR T-cells—genetically modified T-cells (a type of immune cell) meant to target leukemia—have become an established therapy option for children with relapsed or incurable rare form leukemia (B-cell acute lymphoblastic leukemia, or B ALL) in recent years.

The duration of the CAR T-cells in the body is an important component in determining whether the cancer treatment will result in a long-term remission of the leukemia, allowing children to live cancer-free. Until today, little was understood about what causes these cells to survive in the body and, as a result, if the treatment is likely to work long-term without additional treatments.

As part of the CARPALL study, a collaborative research team from 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) to begin to piece together why some CAR T-cells stay in the body long-term.

This study is the first step toward understanding why some CAR T-cells persist. The team intends to expand on the signature revealed in this experiment to find crucial indicators in cell populations and, ultimately, determine whether there is a mechanism to detect, or perhaps produce, CAR T-cells that will survive long-term before therapy begins.

Dr. Nathaniel Anderson, lead author and Marie Sklodowska-Curie Fellow at the Wellcome Sanger Institute, said, “Through cutting-edge single cell genomics, we have, for the first time, been able to crack the code of persistence in CAR T-cells in children with great 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 objective is that this knowledge will eventually allow clinical teams administering CAR T-cell therapies to better predict which patients would respond best to treatments and allow manufacturers to enhance their processes to support persistence, resulting in better patient outcomes.

Dr. Sara Ghorashian, co-senior author, Consultant in Pediatric Hematology at GOSH and Honorary Senior Clinical Lecturer at the UCL GOS ICH, 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 leukemia. 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.”

In-depth research on CAR T-cells

The researchers were able to investigate cells from ten children who participated in a groundbreaking clinical trial (the CARPALL trial) for up to five years following their initial CAR T-cell treatment. This has given them a fresh insight of why some CAR T-cells remain in a patient’s bloodstream while others evaporate, allowing the tumour to recur in some situations.

The scientists were able to establish a distinctive “signature” in long-lasting CAR T-cells by using approaches that analyze individual cells at a genomic level to determine what they do. The signature suggested that long-lasting CAR T-cells in the blood undergo a transformation, allowing them to continue policing the patient’s body for cancer treatment.

This characteristic was found in cells, patients, and adults treated with a different CAR T-cell product for a different form of leukemia. However, it was not found in other types of immune cells. This revealed that the signature discovered by the scientists may not only be a marker of these long-lasting cells, but may also be what permits them to survive in the body and allow for a prolonged remission in children.

The researchers identified crucial genes in CAR T-cells that appeared to allow them to remain in the body for an extended period of time as part of the study. Importantly, these genes will serve as a starting point for future research into identifying markers of persistence in CAR T-cell products as they are manufactured, with the goal of ultimately improving their effectiveness.

Dr. Sam Behjati, co-senior author, Group Lead and Wellcome Senior Research Fellow at the Wellcome Sanger Institute and Honorary Consultant Pediatric Oncologist at 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 leukemia across the world.”

The commitment of research families

Such studies are only possible due to the dedication of the children and families that participate in research. Children had to continue donating cells to the study for up to five years after their initial treatment in order for investigators to evaluate the long-term persistence of cells.

Austin was diagnosed with B ALL when he was two years old, and by the age of eight, he’d had three relapses and significant therapy, including two bone marrow transplants. He had exhausted all conventional therapy choices by the time of his fourth relapse. As part of the CARPALL clinical trial, Austin received an injection of CAR T-cells in October 2016.

Over six years later and Austin, now 14, is still cancer free after treatment, 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. His dad Scott said: “It’s not an exaggeration to say that if it wasn’t for research Austin wouldn’t be alive. The research teams at GOSH gave us so much, we wanted to give something back. Taking part in this study not only gives us that opportunity but we also hope that Austin’s data will help other families like ours in the future.”

“We actually love coming back to GOSH to see the team and keep them a part of our lives. I feel so proud that Austin has been a part of this research journey.”

This ongoing dedication to research is assisting researchers in better understanding new, cutting-edge therapies and improving them for future families.

Dr. Henry Stennett, Research Information Manager at Cancer Research UK, who part-funded the study, said, “We know that immunotherapies such as CAR T-cell therapy have seen some great success over the years, but they don’t work in all patients, and we need to continue to work to figure out why. Studies like this one are vital for bringing us closer to making immunotherapies more effective for more cancer patients.

Source Link