Project Term
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Memorial Sloan Kettering Cancer Center
New York, NY
United States
Project Summary
Chimeric antigen receptor T cell (CAR T) therapy has revolutionized the treatment of multiple myeloma and can lead to deep, long-lasting remissions even in patients with advanced disease. However, some patients experience severe long-term adverse effects, including inflammatory conditions of the gut and brain, Parkinson-like symptoms, and secondary malignancies such as CAR T cell lymphoma, which significantly affect their quality of life. Leveraging one of the world’s largest clinical databases and biorepositories of patients treated with CAR T cells and integrating long-term follow-up with longitudinal and spatially-resolved single-cell multi-omics data, this project seeks to uncover how and why these toxicities develop by tracing the behavior of CAR T cells over time and across different tissues. The insights gained will help improve early diagnosis, prevention, and management of these adverse effects, ultimately making CAR T cell therapy safer and more sustainable for patients.
Lay Abstract
The development of chimeric antigen receptor T cell (CAR T) therapy is one of the most promising recent advances in the treatment of blood cancers, including multiple myeloma, the second-most common blood cancer. In this treatment, a patient’s own immune cells are genetically modified to recognize and destroy cancer cells. These therapies can lead to deep and lasting remissions, even in patients whose disease no longer responds to standard treatments. For some, CAR T therapy offers the first real possibility of a cure. However, as more patients are treated and live longer, scientists are learning that some people develop serious long-term side effects that can greatly affect their quality of life.
While short-term side effects like fever or low blood counts are well known and usually reversible, a growing number of patients experience long-term problems such as prolonged suppression of the immune system, chronic inflammation of the gut, nervous system changes that can resemble Parkinson’s disease, and, in rare cases, the development of new blood cancers that arise directly from CAR T cells. These effects are still poorly understood. They may be caused by the immune cells expanding too much or migrating to parts of the body where they were not intended to go.
Our study aims to understand why these late side effects occur, who is at risk, and how we can prevent or better treat them. We will study one of the world’s largest groups of patients with multiple myeloma treated with CAR T therapy for whom detailed clinical data and long-term follow-up information are available. Using state-of-the-art technology that allows us to analyze individual cells over time, we will track how the CAR T cells behave in the body months and years after treatment. This will help us learn how their presence, growth, and activity are linked to both successful cancer control and harmful side effects.
We will also study treatments that are currently used to manage these side effects. By observing how these therapies affect both the engineered CAR T cells and the patient’s own immune cells, we will identify which approaches help restore balance and which may cause further problems. As CAR T therapy becomes approved for use earlier in a patient’s treatment, including as second-line treatment and even in newly-diagnosed patients, these side effects are being observed more frequently. This is likely due to more patients being treated and the use of “fitter” T cells for manufacturing, which enhances efficacy but can also increase immune activation.
Understanding and preventing these effects is critical to ensure that CAR T therapy remains a safe and potentially curative option for the growing number of patients with multiple myeloma. The insights gained from this research will help improve the early diagnosis, prevention, and treatment of long-term side effects, allowing more patients to live longer, healthier lives after CAR T therapy.
Program