CAR T cells can remain embedded in intestinal tissue long after they disappear from circulation, potentially contributing to a rare but serious gastrointestinal complication of BCMA-directed CAR T-cell therapy.

In the study, researchers investigating CAR T-associated enterocolitis (CAR-TEC) found that the condition involved disruption across multiple components of the intestinal environment – rather than simply the B-cell and plasma-cell depletion caused by treatment. Patients with enterocolitis showed inflammatory changes involving T cells, myeloid cells, stromal cells, and the intestinal epithelium. By contrast, some CAR T-treated patients without enterocolitis had similarly profound B-cell and plasma-cell depletion, suggesting that depletion alone is insufficient to explain the complication.

The team used single-cell and tissue-based analyses to characterize intestinal samples from patients who developed CAR-TEC after BCMA-directed CAR T-cell therapy for multiple myeloma. They identified infiltrating CAR T cells with highly cytotoxic and inflammatory profiles, alongside activation of interferon and JAK–STAT signaling.

Perhaps most strikingly, CAR T cells remained detectable in the intestinal tissue of one patient for more than 2 years after infusion, despite no longer being detectable in peripheral blood or bone marrow. However, not every case appeared to be driven directly by persistent CAR T cells; some patients developed delayed enterocolitis without detectable mucosal CAR T-cell infiltration, pointing to secondary immune dysregulation as another possible mechanism.

“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,” said Saurabh Mehandru, corresponding author of the study, in a press release.

The inflammatory signatures also suggested a potential therapeutic route. Two patients were treated with the selective JAK1 inhibitor upadacitinib and showed improvements in symptoms, fecal calprotectin, and body weight within 4 weeks. In one patient who underwent further analysis, intestinal CAR T-cell density fell from 193 to 39 cells per high-power field after treatment, alongside improvements in several tissue and immune measures.

The researchers said prospective sampling before CAR T-cell infusion will be needed to better establish causality and determine whether targeting persistent mucosal CAR T cells or downstream inflammatory pathways can improve treatment.

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