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Rapid Progression of Adult T-Cell Leukemia/Lymphoma as Tumor Infiltrating Treg Cells after PD-1 Blockade

Daniel A. Rauch, Kevin C. Conlon, Murali Janakiram, Jonathan E. Brammer, John C. Harding, B. Hilda Ye, Xingxing Zang, Xiaoxin Ren, Sydney Olson, Xiaogang Cheng, Milos D. Miljkovic, Hemalatha Sundaramoorthi, Ancy Joseph, Zachary L. Skidmore, Obi Griffith, Malachi Griffith, Thomas A. Waldmann and Lee Ratner

Key Points

  • Clonal expansion in ATLL patients that progressed after nivolumab exposed ATLL cells as tumor-resident Tregs and PD-1 as a suppressor.

  • ATLL clones were infected by HTLV-1 prior to TCR gene rearrangement reveal a previously unappreciated origin from T cell precursors

Abstract

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 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.

  • Submitted June 17, 2019.
  • Revision received August 27, 2019.
  • Accepted August 7, 2019.