Mount Sinai researchers map immune mechanisms behind CAR-T therapy intestinal complications

A team at the Icahn School of Medicine at Mount Sinai has mapped the biological machinery behind a serious intestinal complication that emerges in some patients after CAR-T cell therapy for multiple myeloma. The work, published in Nature Medicine, offers the first detailed picture of what goes wrong in the gut when this happens—and points toward drugs that might prevent or treat it.

CAR-T therapy works by taking a patient's own immune cells, modifying them in the laboratory to recognize cancer, and returning them to the body to hunt down malignant cells. For multiple myeloma, doctors use a version that targets BCMA, a protein on the surface of plasma cells, including the cancerous ones. The therapy has transformed outcomes for patients with blood cancers that were previously difficult to treat. But as the approach becomes more common, clinicians are seeing a troubling side effect: some patients develop persistent gastrointestinal symptoms weeks or months after infusion—diarrhea, abdominal pain, nausea, weight loss. This condition, called CAR-T-associated enterocolitis, is a severe inflammation of the intestinal lining that can persist for months.

The Mount Sinai researchers discovered that CAR-T cells themselves can linger in intestinal tissue long after the treatment is finished, at least in a subset of patients. More importantly, they found that the condition involves far more than a simple loss of immune cells. Patients who developed enterocolitis showed a broad disruption of the intestinal immune environment—changes affecting not just immune cells but also the cells that support intestinal tissue, blood vessels, and the cells that form the intestinal lining itself. The team identified increased activity in JAK-related inflammatory signaling pathways, which help cells communicate and regulate inflammation. This finding matters because JAK inhibitors—drugs that block these proteins—already exist and are used to treat other inflammatory conditions.

What makes the research particularly striking is that some patients without enterocolitis showed similar losses of B cells and plasma cells in the intestinal lining. This suggests that cell loss alone does not explain the condition. Instead, the inflammatory cascade—the way immune cells activate and signal to one another—appears to be the critical factor. Saurabh Mehandru, the study's corresponding author and a gastroenterologist at Mount Sinai, described the work as providing the first detailed map of what happens in the intestine when this complication develops, and identifying pathways that might be targeted therapeutically.

The researchers tested this hypothesis in two patients with CAR-T-associated enterocolitis who received upadacitinib, a JAK1 inhibitor. Both experienced improvements in symptoms, intestinal inflammation, and other measures of disease activity. In one patient, the medication was also associated with a substantial reduction in CAR-T cells in intestinal tissue. These are early results from a small number of patients, but they suggest a direction for future treatment.

Samir Parekh, director of the Center of Excellence for Multiple Myeloma at Mount Sinai and a co-supervisor of the study, emphasized that as CAR-T therapy becomes more widely used and applied earlier in the course of disease, understanding and managing its complications becomes increasingly important. The Mount Sinai findings provide a biological foundation for that work—a map of what goes wrong and a set of potential targets for intervention. The next step will be larger studies to confirm whether JAK inhibitors can reliably prevent or treat this complication, and whether other inflammatory pathways might also be worth targeting.