Long-term Follow-up of Gastrointestinal CAR T-cell Lymphoma: Homing, Clonal Expansion, and Response to Cyclosporine Available to Purchase

• CAR T therapy can drive lymphoma through pre-existing mutations and oncogene integration, with gut-homing a4b7 aiding localization to GI.

• Cyclosporine controlled symptoms and reduced malignant CAR+ clones, showing promise as targeted therapy for CAR T-derived lymphomas.

CAR T-cell therapy has emerged as a transformative treatment for hematological malignancies, yet its potential to drive lymphomagenesis poses significant clinical concerns. In this study, we investigated the mechanisms underlying CAR T-cell-associated lymphomagenesis in the gastrointestinal (GI) tract on a single case, focusing specifically on the role of integrin a4b7 expression and a predisposing somatic SH2B3 mutation. We observed oligoclonal CAR T-cells homing to and clonally expanding in the GI tract, with the dominant expanded clone harboring both a pathogenic SH2B3 mutation and a CAR transgene integration within a TFCP2 locus. The clonal CAR T-cells subsequently transitioned beyond the GI tract into the peripheral blood, suggesting a potential pathway for systemic dissemination. We found clinical, histological, and molecular evidence demonstrating the efficacy of cyclosporine in reducing the expanded malignant clone and achieving durable clinical remission for more than a year. Our findings highlight the complex interplay between CAR T-cell therapy, pre-existing genetic vulnerabilities, and the GI microenvironment, emphasizing the need for vigilant monitoring and tailored therapeutic strategies to address the risks associated with CAR-T lymphomagenesis.