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Leukemia. 2016 Feb;30(2):484-91. doi: 10.1038/leu.2015.214. Epub 2015 Aug 4.

Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism.

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Department of Internal Medicine III, LMU-Klinikum der Universität München, Munich, Germany.
Clinical Co-operation Group Immunotherapy at the Helmholtz Zentrum München, Munich, Germany.
AMGEN Research (Munich) GmbH, Munich, Germany.
Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
German Cancer Consortium (DKTK), Heidelberg, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Oncology, Dr von Haunersches Kinderspital, Ludwig Maximilians-Universität (LMU), Munich, Germany.
Institute for Immunology, Ludwig-Maximilians-Universität, Munich, Germany.


Bispecific T-cell engagers (BiTEs) are very effective in recruiting and activating T cells. We tested the cytotoxicity of the CD33/CD3 BiTE antibody construct AMG 330 on primary acute myeloid leukemia (AML) cells ex vivo and characterized parameters contributing to antileukemic cytolytic activity. The E:T ratio and the CD33 expression level significantly influenced lysis kinetics in long-term cultures of primary AML cells (n=38). AMG 330 induced T-cell-mediated proinflammatory conditions, favoring the upregulation of immune checkpoints on target and effector cells. Although not constitutively expressed at the time of primary diagnosis (n=123), PD-L1 was strongly upregulated on primary AML cells upon AMG 330 addition to ex vivo cultures (n=27, P<0.0001). This phenomenon was cytokine-driven as the sole addition of interferon (IFN)-γ and tumor necrosis factor-α also induced expression. Through blockade of the PD-1/PD-L1 interaction, AMG 330-mediated lysis (n=9, P=0.03), T-cell proliferation (n=9, P=0.01) and IFN-γ secretion (n=8, P=0.008) were significantly enhanced. The combinatorial approach was most beneficial in settings of protracted AML cell lysis. Taken together, we have characterized a critical resistance mechanism employed by primary AML cells under AMG 330-mediated proinflammatory conditions. Our results support the evaluation of checkpoint molecules in upcoming clinical trials with AMG 330 to enhance BiTE antibody construct-mediated cytotoxicity.

[Indexed for MEDLINE]

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