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

• Published in: Leukemia Vol. 30; no. 2; pp. 484 - 491
• Main Authors: 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, Bauerle, P A, Hiddemann, W, Riethmüller, G, Subklewe, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2016; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/21; 13/31; 631/250/580; 631/67/1059/2325; 631/67/1059/602; 631/67/1990/283/1897; 64/60; Acute myeloid leukemia; Animals; Antibodies; Antibodies, Bispecific - pharmacology; Anticancer properties; B7-H1 Antigen - analysis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - physiology; Cancer Research; CD3 antigen; Cell proliferation; Cellular proteins; Clinical trials; Combinatorial analysis; Critical Care Medicine; Cytokines; Cytolytic activity; Cytotoxicity; Effector cells; Gene expression; Genetic aspects; Health aspects; Hematology; Humans; Immune checkpoint; Immune evasion; Immune response; Inflammation; Intensive; Interferon; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - pathology; Lymphocytes; Lymphocytes T; Lysis; Medicine; Medicine & Public Health; Mice; Oncology; original-article; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - analysis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - physiology; Regulation; Sialic Acid Binding Ig-like Lectin 3 - analysis; T cells; T-Lymphocytes - immunology; Toxicity testing; Tumor Escape - drug effects; Tumor necrosis factor-α; γ-Interferon; Germany
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2015.214

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.