In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 24 ( 2005-12-15), p. 11712-11720
Abstract:
SGN-40, a humanized immoglobulin G1 (IgG1) anti-CD40 monoclonal antibody, mediates cytotoxicity against human multiple myeloma (MM) cells via suppression of interleukin (IL)-6–induced proliferative and antiapoptotic effects as well as antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we studied the clinical significance of an immunomodulatory drug lenalidomide on SGN-40–induced cytotoxicity against CD138+CD40+ MM lines and patient MM cells. Pretreatment with lenalidomide sensitized MM cells to SGN-40–induced cell death. Combined lenalidomide and SGN-40 significantly induced MM apoptosis, evidenced by enhanced cleavage of caspase-3/8/poly(ADP-ribose)polymerase and increased sub-G0 cells, compared with either single agent at the same doses. Pretreatment of effector cells with lenalidomide augmented SGN-40–induced MM cell lysis, associated with an increased number of CD56+CD3− natural killer (NK) cells expressing CD16 and LFA-1. Importantly, pretreatment with lenalidomide or lenalidomide and SGN-40 markedly enhanced NK-cell–mediated lysis of autologous patient MM cells triggered by SGN-40. Lenalidomide also up-regulated CD40L on CD56+CD3− NK cells, facilitating IL-2–mediated activation of NK cells. In addition, lenalidomide induced the CD56dim NK subset, which are more potent mediators of ADCC against target MM cells than the CD56bright NK subset. Finally, pretreatment of both effector and target MM cells with lenalidomide markedly enhanced SGN-40–mediated ADCC against CD40-expressing MM cells. These studies, therefore, show that the addition of lenalidomide to SGN-40 enhances cytotoxicity against MM cells, providing the framework for combined lenalidomide and SGN-40 in a new treatment paradigm to both target MM cells directly and induce immune effectors against MM. (Cancer Res 2005; 65(24): 11712-20)
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-05-1657
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2005
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
