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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.

Author information

1
Department of Internal Medicine III, LMU-Klinikum der Universität München, Munich, Germany.
2
Clinical Co-operation Group Immunotherapy at the Helmholtz Zentrum München, Munich, Germany.
3
AMGEN Research (Munich) GmbH, Munich, Germany.
4
Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
5
German Cancer Consortium (DKTK), Heidelberg, Germany.
6
German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Department of Oncology, Dr von Haunersches Kinderspital, Ludwig Maximilians-Universität (LMU), Munich, Germany.
8
Institute for Immunology, Ludwig-Maximilians-Universität, Munich, Germany.

Abstract

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.

PMID:
26239198
DOI:
10.1038/leu.2015.214
[Indexed for MEDLINE]

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