Abstract
Purpose: To establish a proof-of-concept for the efficacy of the anti-CD38 antibody daratumumab in the poor prognosis CD38+ chronic lymphocytic leukemia (CLL) subtype.Experimental Design: The mechanism of action of daratumumab was assessed in CLL primary cells and cell lines using peripheral blood mononuclear cells to analyze antibody-dependent cell cytotoxicity (ADCC), murine and human macrophages to study antibody-dependent cell phagocytosis (ADCP), or human serum to analyze complement-dependent cytotoxicity (CDC). The effect of daratumumab on CLL cell migration and adhesion to extracellular matrix was characterized. Daratumumab activity was validated in two in vivo models.Results: Daratumumab demonstrated efficient lysis of patient-derived CLL cells and cell lines by ADCC in vitro and ADCP both in vitro and in vivo whereas exhibited negligible CDC in these cells. To demonstrate the therapeutic effect of daratumumab in CLL, we generated a disseminated CLL mouse model with the CD38+ MEC2 cell line and CLL patient-derived xenografts (CLL-PDX). Daratumumab significantly prolonged overall survival of MEC2 mice, completely eliminated cells from the infiltrated organs, and significantly reduced disease burden in the spleen of CLL-PDX. The effect of daratumumab on patient-derived CLL cell dissemination was demonstrated in vitro by its effect on CXCL12-induced migration and in vivo by interfering with CLL cell homing to spleen in NSG mice. Daratumumab also reduced adhesion of CLL cells to VCAM-1, accompanied by downregulation of the matrix metalloproteinase MMP9.Conclusions: These unique and substantial effects of daratumumab on CLL viability and dissemination support the investigation of its use in a clinical setting of CLL. Clin Cancer Res; 23(6); 1493-505. ©2016 AACR.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and is characterized by progressive accumulation of nonfunctional, apoptosis-resistant mature B cells in peripheral blood, bone marrow, and lymphoid tissues [1, 2]
Daratumumab induces antibodydependent cell cytotoxicity (ADCC) Antibody-dependent killing via ADCC by FcgR-bearing effector cells accounts for the antitumor activity of daratumumab in models of multiple myeloma and Burkitt lymphoma [20, 30]
The ability of daratumumab to induce ADCC on CLL cells was assessed by calcein-AM release assay using PBMCs from healthy donors as a source of effector cells
Summary
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and is characterized by progressive accumulation of nonfunctional, apoptosis-resistant mature B cells in peripheral blood, bone marrow, and lymphoid tissues [1, 2]. Heavy-water experiments have shown that CLL contains a small fraction of actively proliferating cells, with approximately 2% of cells newly generated each day [3]. This proliferation occurs in specific structures known as proliferation centers localized in the lymph nodes and in the bone marrow. CLL is considered a disease characterized by a dynamic balance between cells circulating in the blood and cells located in permissive niches in lymphoid organs [1, 2] The former are primarily mature-looking small lymphocytes resistant to apoptosis, whereas the latter are composed by lymphocytes that undergo either proliferation or apoptosis depending on the microenvironment
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