PuSH - Publikationsserver des Helmholtz Zentrums München

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 möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Leukemia
Quellenangaben Band: 30, Heft: 2, Seiten: 484-491 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CCG Hematopoetic Cell Transplants (IMI-KHZ)
Research Unit Gene Vector (AGV)
CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)