Targeting CD38 in acute myeloid leukemia interferes with leukemia trafficking and induces phagocytosis

Meike Farber,H Christian Reinhardt,Lucas Arnold,Michael Möllmann,Yiyang Chen,Ulrich Dührsen,Eva Boog-Whiteside,Maher Hanoun,Yu-An Lin

doi:10.1038/s41598-021-01300-8

Meike Farber, H Christian Reinhardt + Show 7 more

Open Access

https://doi.org/10.1038/s41598-021-01300-8

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Abstract

Targeting the interaction between leukemic cells and the microenvironment is an appealing approach to enhance the therapeutic efficacy in acute myeloid leukemia (AML). AML infiltration induces a significant release of inflammatory cytokines in the human bone marrow niche which accelerates leukemogenesis. As the transmembrane glycoprotein CD38 has been shown to regulate cytokine release, we assessed the anti-leukemic potential of CD38 inhibition in AML. CD38 expression in AML cells proved to depend on microenvironmental cues and could be significantly enforced through addition of tretinoin. In fact, the anti-CD38 antibody daratumumab showed significant cytostatic efficacy in a 3D in vitro triple-culture model of AML, but with modest cell-autonomous cytotoxic activity and independent of CD38 expression level. In line with a predominantly microenvironment-mediated activity of daratumumab in AML, CD38 inhibition significantly induced antibody-dependent phagocytosis and showed interference with AML cell trafficking in vivo in a xenograft transplantation model, but overall lacked robust anti-leukemic effects.

Highlights

Targeting the interaction between leukemic cells and the microenvironment is an appealing approach to enhance the therapeutic efficacy in acute myeloid leukemia (AML)
CD38 inhibition results in high anti‐leukemic efficacy in vitro independent of CD38 expression level
To test its clinical relevance, we treated a number of primary human AML or peripheral blood mononuclear cells from healthy donors with 0.1 μg/ml daratumumab

Summary

Introduction

Targeting the interaction between leukemic cells and the microenvironment is an appealing approach to enhance the therapeutic efficacy in acute myeloid leukemia (AML). AML infiltration induces a significant release of inflammatory cytokines in the human bone marrow niche which accelerates leukemogenesis. The anti-CD38 antibody daratumumab showed significant cytostatic efficacy in a 3D in vitro triple-culture model of AML, but with modest cell-autonomous cytotoxic activity and independent of CD38 expression level. In line with a predominantly microenvironmentmediated activity of daratumumab in AML, CD38 inhibition significantly induced antibody-dependent phagocytosis and showed interference with AML cell trafficking in vivo in a xenograft transplantation model, but overall lacked robust anti-leukemic effects. AML infiltration induced a significant release of inflammatory cytokines in the human bone marrow, which proved to accelerate leukemogenesis[7]. We show that CD38 inhibition leads to significant cytostatic efficacy in a 3D in vitro triple-culture model of AML, with modest cell autonomous cytotoxic activity. Daratumumab significantly induces antibody dependent phagocytosis in AML and shows interference with AML cell trafficking in vivo in a xenograft transplantation model

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