Targeting CD38 with daratumumab is lethal to Waldenström macroglobulinaemia cells.

Autor: Paulus A; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA., Manna A; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA., Akhtar S; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA., Paulus SM; Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA., Sharma M; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA., Coignet MV; Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA., Jiang L; Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA., Roy V; Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA., Witzig TE; Division of Hematology, Mayo Clinic, Rochester, MN, USA.; Division of Hematopathology, Mayo Clinic, Rochester, MN, USA., Ansell SM; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Allan J; Department of Medicine, Weill Cornell Medical College, Cornell, NY, USA., Furman R; Department of Medicine, Weill Cornell Medical College, Cornell, NY, USA., Aulakh S; Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA., Manochakian R; Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA., Ailawadhi S; Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA., Chanan-Khan AA; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.; Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA., Sher T; Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA.
Jazyk: angličtina
Zdroj: British journal of haematology [Br J Haematol] 2018 Oct; Vol. 183 (2), pp. 196-211. Date of Electronic Publication: 2018 Aug 06.
DOI: 10.1111/bjh.15515
Abstrakt: CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti-CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib-resistant lines) elicited antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI-WM1-xenografted mice. CD38 is reported to augment B-cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib-resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single-agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti-WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co-targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.
(© 2018 British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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