Researchers at the Icahn School of Medicine at Mount Sinai have identified biological mechanisms that may contribute to CAR-T cell-associated enterocolitis, a serious inflammatory condition of the intestine that can occur after a type of CAR-T cell therapy for multiple myeloma.
Published September 23 in Nature Medicine, the study found that CAR-T cells can persist in the intestinal tissue long after treatment and that patients who develop enterocolitis experience widespread changes in the immune system within the gut. The researchers also identified inflammatory pathways that may offer potential treatment targets.
CAR-T cell therapy uses a patient's own immune cells, called T cells, that are genetically modified to recognize and attack cancer cells. A version of the therapy known as BCMA-directed CAR-T targets a protein called BCMA found on plasma cells, including the cancerous plasma cells involved in multiple myeloma. Some patients treated with these therapies develop persistent gastrointestinal symptoms, including diarrhea, abdominal pain, nausea, and weight loss.
"CAR-T therapy has transformed outcomes for many patients with blood cancers, but as these treatments become more widely used, we are also learning more about their long-term effects on the immune system," said Saurabh Mehandru, MD, Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai and corresponding author of the study. "Our research provides the first detailed map of what happens in the intestine in patients who develop CAR-T-associated enterocolitis and identifies biological pathways that may be targeted therapeutically"
"CAR-T cell therapy has changed the treatment landscape for multiple myeloma, giving patients with difficult-to-treat disease new treatment options," said Samir Parekh, MD, Professor of Medicine and Director of the Center of Excellence for Multiple Myeloma at the Icahn School of Medicine at Mount Sinai, and co-supervisor of the study. "As we use these therapies in more patients and earlier in the course of disease, it is increasingly important to understand and manage the complications that can occur. These findings provide important insight into why some patients develop severe intestinal inflammation and point to potential strategies for treating or preventing this complication."
Key Findings
- CAR-T cells can persist in the intestine long after treatment in a subset of patients.
- CAR-T-associated enterocolitis involves more than the loss of protective immune cells. Patients with CAR-T-associated enterocolitis had substantial loss of B cells and plasma cells in the intestinal lining. However, some patients who did not develop enterocolitis had similar changes, indicating that this loss alone does not explain the condition.
- Multiple types of cells in the intestine are affected, including immune cells, cells that support intestinal tissue and blood vessels, and the cells lining the intestine, suggesting widespread disruption of the intestinal immune environment.
- The researchers identified inflammatory pathways that may offer potential treatment targets. JAK proteins help cells communicate and regulate inflammation. The study found increased activity of JAK-related inflammatory signaling across multiple cell types in the intestine.
"This work provides a detailed view of the cellular changes associated with CAR-T-associated enterocolitis and shows that the condition involves multiple components of the intestinal immune environment," said Nikhit Kethidi, MD, first authors of the study. "Understanding these changes may help identify new approaches to treating this complication and guide future studies of how to prevent or manage it."
The findings also point to a potential approach to treatment. JAK inhibitors are medications that block proteins involved in inflammatory signaling. Two patients with CAR-T-associated enterocolitis who received upadacitinib, a medication that blocks JAK1, experienced improvements in symptoms, intestinal inflammation, and other measures of disease activity. In one patient, treatment was also associated with a substantial reduction in CAR-T cells in intestinal tissue.
The study was conducted by investigators from the Icahn School of Medicine at Mount Sinai in collaboration with researchers from Weill Cornell Medicine, Johns Hopkins University, Memorial Sloan Kettering Cancer Center, Stanford University School of Medicine, Harvard Medical School and Boston Children's Hospital, Northwestern University Feinberg School of Medicine, Charité–Universitätsmedizin Berlin, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Leipzig, and other national and international institutions.
