title: Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications.
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-G(0) 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 CD56(dim) NK subset, which are more potent mediators of ADCC against target MM cells than the CD56(bright) 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.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Xian-Feng
authors.initials: XF
authors.lastname: Li
authors.forename: Laurence
authors.initials: L
authors.lastname: Catley
authors.forename: Rory
authors.initials: R
authors.lastname: Coffey
authors.forename: Iris
authors.initials: I
authors.lastname: Breitkreutz
authors.forename: Jooeun
authors.initials: J
authors.lastname: Bae
authors.forename: Weihua
authors.initials: W
authors.lastname: Song
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Robert
authors.initials: R
authors.lastname: Schlossman
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Iqbal S
authors.initials: IS
authors.lastname: Grewal
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis / Q000187:drug effects*; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology; D019002:CD56 Antigen / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D006801:Humans; D007116:Immunization, Passive; D015850:Interleukin-6 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D019002:CD56 Antigen; D015850:Interleukin-6; D023201:CD40 Ligand; D013792:Thalidomide; D000077269:Lenalidomide