First European trial tests CAR T therapy in amyloidosis patients

Three patients with light chain amyloidosis have been treated with CAR T cell therapy in the first European clinical trial testing the safety and efficacy of this immunotherapy in this patient group, led by UCL and UCLH researchers.

The ALARIC trial, which was developed within the UK Myeloma Research Alliance and is supported by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre, aims to treat at least 12 patients at UCLH over the next two years and will also shortly open in Leeds.

Light chain amyloidosis (AL) is a rare but serious blood disease affecting around 500 people in the UK each year. It develops when abnormal immune plasma cells produce faulty "light chain" proteins that misfold and accumulate in tissues and organs. Without treatment, the condition can lead to organ failure and can be life-threatening. There is currently no cure.

The standard treatment for AL amyloidosis is chemotherapy. While often effective, it involves weekly infusions for six months followed by regular maintenance therapy for up to 18 months. Chemotherapy can cause significant side effects, and the impact on patients' quality of life during prolonged treatment can be considerable.

Moreover, there is no licensed treatment for patients whose disease does not respond to chemotherapy or who relapse, highlighting the urgent need for new options.

CAR T-cell therapy represents a fundamentally different approach. It involves collecting a patient's own T cells (a type of immune cell) and genetically modifying them in a laboratory so they can recognise and destroy the abnormal plasma cells producing amyloid-forming proteins. The therapy targets proteins such as B-cell maturation antigen (BCMA), which are present on these harmful cells.

CAR T therapy has already proven effective in treating multiple myeloma, a related blood cancer in which abnormal plasma cells also express BCMA. If successful, the therapy could offer patients a one-off treatment with a high and durable response rate. By suppressing the abnormal cells at their source, it may also give damaged organs a better chance to recover.

Principal investigator of the study and consultant haematologist at UCLH, Dr Lydia Lee (UCL Cancer Institute) said: "For patients with relapsed or refractory AL amyloidosis, treatment options are extremely limited, and their disease is likely to progress causing suffering and even death.

"CAR T-cell therapy has transformed outcomes in multiple myeloma, and we are hopeful it could have a similarly significant impact in amyloidosis. This trial is an important first step in evaluating whether we can safely and effectively use this highly targeted therapy to eliminate the cells that drive this disease."

Chief investigator of the study Professor Ashutosh Wechalekar (UCL Medicine), who is also a consultant hematologist at UCLH and the Royal Free London NHS Trust, said: "This is a phase one study, so our first priority is safety. However, the scientific rationale is strong. The abnormal plasma cells in AL amyloidosis express the same target protein that we successfully treat in myeloma. If we can interrupt the disease process at its source, we may be able not only to control the condition but also to improve patients' quality of life."

Professor Allan Hackshaw (Director of CRUK & UCL Cancer Trials Centre, UCL Cancer Institute) added: "ALARIC is an example of successful cross-sector working in non-commercial research, with it being sponsored by UCL - which sponsors the largest number of advanced therapy cancer trials in the UK - and delivered via the Cancer Research UK and UCL Cancer Trials Centre."

Patient's story

Tim Wiberg, 61, of Sheffield, is the third patient to receive CAR T-cell therapy as part of the ALARIC trial. He first noticed something was wrong nearly two years ago when his urine became persistently frothy. Although he felt well, tests eventually revealed protein in his urine. After months of investigations and a kidney biopsy, he was diagnosed with AL amyloidosis

Physically, Tim had few symptoms. "From the very beginning, the only sign that something wasn't right was protein in my urine," he said. "Apart from that, I've managed to stay fit, which has been a real blessing."

The emotional impact, however, was significant. "A diagnosis like this takes time to sink in. I'm not sure I've fully come to terms with it even now. It's a life-changing disease."

Tim underwent six months of weekly chemotherapy. Although it reduced the disease, the response was only partial.

"It was tough. Not unbearable, but relentless," he said. "The chemotherapy was combined with steroids, which I found particularly hard. Sleep became a real problem. It took over my life for those six months."

When he was offered the opportunity to join the CAR T-cell trial, he initially felt uncertain. After careful consideration, he decided to take part.

"The standard treatment had only gone so far, and it felt as though the options were beginning to narrow," he said. "This trial offered something different - a new and innovative way of tackling the disease. Yes, there are risks, but there is also hope. Being offered a place made me feel far more positive.

"It feels like a genuine opportunity, not just for me, but for others who may face this diagnosis in the future. If my experience can help move things forward, then it feels worth sharing."

Tim received his CAR T cells on 2 March and is currently recovering at home.

Of the experience, he said: "The chemotherapy before the immunotherapy was challenging, it gave me pretty bad nausea which stayed with me for quite a while. The immunotherapy was unproblematic and I recovered very quickly from that. I was in hospital for two weeks and I can honestly say the hardest part was being woken up every few hours for nurses to get my vitals. But they were absolutely wonderful, I cannot fault the care.

"Amyloidosis is mainly measured by the prevalence of some bad proteins called lambda light chains. At my worst, before any treatment, I had around 200. And after the infusion, they are now almost immeasurable. So that really says it all."

Source:

University College London