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

• DOI: 10.1038/leu.2015.214
• Publication Date: 2015-08-04T11:32:45Z
• Authors: C Krupka; P Kufer; R Kischel; G Zugmaier; F S Lichtenegger; T Köhnke; B Vick; I Jeremias; K H Metzeler; T Altmann; S Schneider; M Fiegl; K Spiekermann; P A Bauerle; W Hiddemann; G Riethmüller; M Subklewe
• Keywords: Leukemia, Myeloid, Acute; Mice; 03 medical and health sciences; 0302 clinical medicine; T-Lymphocytes; Antibodies, Bispecific; Programmed Cell Death 1 Receptor; Sialic Acid Binding Ig-like Lectin 3; Animals; Humans; Tumor Escape; B7-H1 Antigen

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.