Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade.

Rauch, Daniel A.; Conlon, Kevin C; Janakiram, Murali; Brammer, Jonathan E; Harding, John C; Ye, B Hilda; Zang, Xingxing; Ren, Xiaoxin; Olson, Sydney; Cheng, Xiaogang; Miljkovic, Milos D; Sundaramoorthi, Hemalatha; Joseph, Ancy; Skidmore, Zachary L; Griffith, Obi; Griffith, Malachi; Waldmann, Thomas A; Ratner, Lee (2019). Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade. Blood, 134(17), pp. 1406-1414. American Society of Hematology 10.1182/blood.2019002038

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Immune checkpoint inhibitors are a powerful new tool in the treatment of cancer, with prolonged responses in multiple diseases, including hematologic malignancies, such as Hodgkin lymphoma. However, in a recent report, we demonstrated that the PD-1 inhibitor nivolumab led to rapid progression in patients with adult T-cell leukemia/lymphoma (ATLL) (NCT02631746). We obtained primary cells from these patients to determine the cause of this hyperprogression. Analyses of clonality, somatic mutations, and gene expression in the malignant cells confirmed the report of rapid clonal expansion after PD-1 blockade in these patients, revealed a previously unappreciated origin of these malignant cells, identified a novel connection between ATLL cells and tumor-resident regulatory T cells (Tregs), and exposed a tumor-suppressive role for PD-1 in ATLL. Identifying the mechanisms driving this alarming outcome in nivolumab-treated ATLL may be broadly informative for the growing problem of rapid progression with immune checkpoint therapies.

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