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Krupka, C. ; Kufer, P.* ; Kischel, R.* ; Zugmaier, G.* ; Lichtenegger, F.S. ; Köhnke, T. ; Vick, B. ; Jeremias, I. ; Metzeler, K.H.* ; Altmann, T. ; Schneider, S.* ; Fiegl, M.* ; Spiekermann, K.* ; Baeuerle, P.A.* ; Hiddemann, W.* ; Riethmüller, G.* ; Subklewe, M.

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.

Leukemia 30, 484-491 (2016)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 AML cells ex vivo and characterized parameters contributing to anti-leukemic 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 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 IFN-γ and TNF-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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Acute Myeloid-leukemia; Single-chain Antibody; Hematologic Malignancies; Cancer-immunotherapy; Engaging Antibody; Blast Cells; Expression; Stimulation; Inhibition; Ligands
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 30, Issue: 2, Pages: 484-491 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CCG Hematopoetic Cell Transplants (IMI-KHZ)
Research Unit Gene Vector (AGV)
CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)