Mount Sinai scientists have become the first to report a potentially serious side effect related to a new form of immunotherapy known as CAR-T cell therapy, which was recently approved for the treatment of multiple myeloma. Their findings were published as a case study in Nature Medicine in December.
Multiple myeloma is a complex and incurable type of blood plasma cancer that often requires multiple treatments as the disease progresses and becomes resistant to previous therapies, often resulting in chronic disease with periods of acute illness.
CAR-T cell therapy uses genetically engineered immune system cells known as chimeric antigen receptor (CAR) T cells. In the specific version at issue, the CAR-T cells were used to target a protein known as B cell maturation antigen (BCMA). BCMA is commonly found in multiple myeloma, and this therapy has shown impressive response rates in people with particularly complex, treatment-resistant multiple myeloma.
More than three months after finishing a course of BCMA-targeted CAR-T cell therapy, the patient described in the Mount Sinai case study started showing progressive neurological features of symptoms resembling Parkinson’s disease, including tremors as well as handwriting and gait changes. The patient later died due to complications from infection, and researchers found evidence of BCMA protein in the brain’s basal ganglia and scarring in that area, suggesting that this serious side effect may have been due to the therapy targeting the BCMA in the brain.
“Our findings will impact the risk-benefit assessment of BCMA-targeted CAR-T cell therapy for multiple myeloma and have already led to improved monitoring and proactive management of neurologic adverse events across clinical trials of BCMA-targeted therapy,” said Oliver Van Oekelen, MD, PhD student at the Icahn School of Medicine at Mount Sinai and the first author of the manuscript.
Samir Parekh, MBBS, Professor of Medicine (Hematology and Medical Oncology), and Oncological Sciences, at Icahn Mount Sinai and the corresponding author of the case study, adds, “This study showed that BCMA-targeted CAR-T cell therapy can cross the blood-brain barrier at least in a subset of patients to cause a progressive neurocognitive and movement disorder. This shows that CAR-T cell therapies, although effective in multiple myeloma, warrant close monitoring for neurotoxicity, especially as such treatments acquire more widespread implementation in multiple myeloma patients.”
BCMA-targeted CAR-T therapy and similar immunotherapies are being used or tested in other types of cancers, underscoring the importance of this study’s findings.
In this study, researchers analyzed clinical data, blood, spinal fluid, and brain samples after the CAR-T infusion. Mount Sinai’s Human Immune Monitoring Center, led by Miriam Merad, MD, PhD, found CAR-T cells in the blood and spinal fluid, leading scientists to believe this phenomenon led to the CAR-T cells targeting the basal ganglia and infiltrating the brain to cause the Parkinson’s-like symptoms.
Though these findings are limited by the inherent fact that this is a case study on a single patient’s reaction, a clinical trial of a BMCA-targeted CAR-T therapy has also reported that five percent of patients in the trial experienced movement and neurocognitive treatment-related adverse effects. Researchers also found evidence of BCMA expression in the brains of healthy individuals.
The study was a result of a multi-disciplinary effort between myeloma physicians, neurologists, radiologists, pathologists, and immunologists from Mount Sinai and was funded by National Cancer Institute grants R01 CA244899 and CA252222.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City’s largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai advances medicine and health through unrivaled education and translational research and discovery to deliver care that is the safest, highest-quality, most accessible and equitable, and the best value of any health system in the nation. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture ambulatory surgery centers; more than 415 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. The Mount Sinai Hospital is ranked on U.S. News & World Report’s “Honor Roll” of the top 20 U.S. hospitals and is top in the nation by specialty: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. Mount Sinai Kravis Children’s Hospital is ranked in U.S. News & World Report’s “Best Children’s Hospitals” among the country’s best in four out of 10 pediatric specialties. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report’s “Best Medical Schools,” aligned with a U.S. News & World Report “Honor Roll” Hospital, and No. 14 in the nation for National Institutes of Health funding. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.