Light chain (AL) amyloidosis is a rare but serious blood disease that develops when aberrant immune plasma cells produce abnormal “light chain” proteins. These proteins misfold and accumulate in tissues and organs. When untreated, it can cause organ failure and death.
Although therapies have improved over the past decade, there have been no FDA-approved treatments for patients when AL amyloidosis develops resistance or returns (relapses) after other therapies fail.
Now MSK cellular therapist Heather J. Landau, MD, reports dramatic results from a phase 1 clinical trial showing that a chimeric antigen receptor (CAR) T cell therapy appears to be effective at stopping AL amyloidosis in these patients. CAR T cell therapy is an approach in which scientists genetically engineer a patient’s own immune cells to make a new protein, turning them into supercharged cancer fighters.
The treatment appears to be safe and to work fast: In patients receiving the therapy, key biomarkers returned to normal levels within one to two weeks, and no lingering cancer cells could be detected. Dr. Landau, who led the study, is presenting the findings at the 2025 annual meeting of the American Society of Clinical Oncology (ASCO).
“With patients going into such deep remissions, this CAR T cell treatment really has the potential to change the trajectory of this disease,” Dr. Landau says. “I’ve seen very sick patients have an amazing recovery in a short time.”
Clinical Trial Targeting BCMA Stops Disease Progression
The CAR T cell therapy, called NXC-201, targets a protein called BCMA, which is expressed on the surface of amyloid plasma cells and drives cancer growth. In the first 10 patients to receive the therapy:
- An important disease marker called “free light chain” returned to normal for every patient within 7 to 15 days.
- In 8 out of 9 patients tested for minimal residual disease (the presence of a very small number of cancer cells remaining after treatment), there were no disease cells detected in the bone marrow after 25 days.
- No patients have relapsed since treatment, which occurred as long as one year ago.
- Side effects were manageable, with no serious toxicity.
Filling a Gap in Treatment
Despite the urgent need for better AL amyloidosis treatments, progress has been slow, Dr. Landau explains. Pharmaceutical companies have not had a strong incentive to develop and test treatments for such a rare disease — especially in patients at high risk of death from organ failure.
With patients going into such deep remissions, this CAR T cell treatment really has the potential to change the trajectory of this disease.
Heather J. Landaucellular therapist
Drugs that treat a similar plasma cell disease, multiple myeloma, can sometimes be effective in people with AL amyloidosis. By far, the most important of these drugs is daratumumab (Darzalex), a monoclonal antibody that targets a protein called CD38. In 2021, the FDA approved it for AL amyloidosis when given in combination with several other drugs. This remains the only FDA-approved treatment option for patients with the disease.
“We know if we can get this disease into remission, patients can do really, really well,” Dr. Landau says. “Sixty percent of newly diagnosed patients respond to daratumumab, which has been transformative for the field,”
Unfortunately, 40% of patients have a less-than-ideal response to daratumumab, and some of those patients will require additional treatment. Even among the 60% who do respond, about one-third will relapse. “That created even more impetus to test other treatments, especially CAR T because it needs to be given only once,” Dr. Landau says.
Advantages of CAR T Cell Treatment
Scientists were optimistic that a CAR T cell therapy targeting the BCMA protein could be effective against AL amyloidosis. BCMA is highly expressed on amyloidogenic plasma cells. In addition, the treatment already had worked well against multiple myeloma. In fact, the first AL amyloidosis patients to receive NCX-201 were enrolled in a trial focused on treating multiple myeloma.
When the treatment appeared safe and effective in those AL amyloidosis patients, the current trial, called NEXICART-2 and sponsored by Nexcella Inc., began at MSK and is now open at six other sites. The trial has the goal of eventually enrolling 40 AL amyloidosis patients.
Dr. Landau says BCMA CAR T cell therapy is especially well-suited for people with this disease because they often are frail due to impaired organs. Most other therapies require ongoing treatment and result in side effects.
The trial will continue enrolling more patients to confirm safety and effectiveness. But results so far are impressive, given the rapid and sustained reduction of the disease marker in the blood in all patients treated.
“The second patient in the trial was a woman who had gone through two stem cell transplants, had very toxic disease and was struggling to walk,” Dr. Landau says. “Just a few weeks after receiving the cells, she was comfortably walking several miles. Now she is living her best life and traveling the world.”
The clinical trial is sponsored by Nexcella, Inc.