Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab
- 14 December 2017
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 23 (24), 7498-7511
- https://doi.org/10.1158/1078-0432.ccr-17-2027
Abstract
Purpose: Daratumumab treatment results in a marked reduction of CD38 expression on multiple myeloma cells. The aim of this study was to investigate the clinical implications and the underlying mechanisms of daratumumab-mediated CD38 reduction. Experimental Design: We evaluated the effect of daratumumab alone or in combination with lenalidomide-dexamethasone, on CD38 levels of multiple myeloma cells and nontumor immune cells in the GEN501 study (daratumumab monotherapy) and the GEN503 study (daratumumab combined with lenalidomide-dexamethasone). In vitro assays were also performed. Results: In both trials, daratumumab reduced CD38 expression on multiple myeloma cells within hours after starting the first infusion, regardless of depth and duration of the response. In addition, CD38 expression on nontumor immune cells, including natural killer cells, T cells, B cells, and monocytes, was also reduced irrespective of alterations in their absolute numbers during therapy. In-depth analyses revealed that CD38 levels of multiple myeloma cells were only reduced in the presence of complement or effector cells, suggesting that the rapid elimination of CD38high multiple myeloma cells can contribute to CD38 reduction. In addition, we discovered that daratumumab–CD38 complexes and accompanying cell membrane were actively transferred from multiple myeloma cells to monocytes and granulocytes. This process of trogocytosis was also associated with reduced surface levels of some other membrane proteins, including CD49d, CD56, and CD138. Conclusions: Daratumumab rapidly reduced CD38 expression levels, at least in part, through trogocytosis. Importantly, all these effects also occurred in patients with deep and durable responses, thus excluding CD38 reduction alone as a mechanism of daratumumab resistance. The trials were registered at www.clinicaltrials.gov as NCT00574288 (GEN501) and NCT1615029 (GEN503). Clin Cancer Res; 23(24); 7498–511. ©2017 AACR.Keywords
Other Versions
This publication has 47 references indexed in Scilit:
- The CD49d/CD29 complex is physically and functionally associated with CD38 in B-cell chronic lymphocytic leukemia cellsLeukemia, 2012
- Evidence for a macromolecular complex in poor prognosis CLL that contains CD38, CD49d, CD44 and MMP‐9British Journal of Haematology, 2011
- Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological TumorsThe Journal of Immunology, 2011
- Dynamics of Macrophage Trogocytosis of Rituximab-Coated B CellsPLOS ONE, 2011
- Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumabHaematologica, 2010
- Monoclonal antibodies: versatile platforms for cancer immunotherapyNature Reviews Immunology, 2010
- Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myelomaOncogene, 2008
- CD38/CD19: a lipid raft–dependent signaling complex in human B cellsBlood, 2007
- What is trogocytosis and what is its purpose?Nature Immunology, 2003
- Studies on the mechanism of phagocytosis. II. The interaction of macrophages with anti-immunoglobulin IgG-coated bone marrow-derived lymphocytes.The Journal of Experimental Medicine, 1976