title: Lenalidomide enhances antibody-dependent cellular cytotoxicity of solid tumor cells in vitro: influence of host immune and tumor markers.
abstract: We evaluated the effect of combining lenalidomide with therapeutic antibodies on antibody-dependant cell-mediated cytotoxicity (ADCC) of solid tumor cells, and the requirement for expression of natural killer (NK) cell-activating receptors and their solid tumor surface ligands. Twenty-three human tumor cell lines (colon, breast, lung, head and neck, ovary, and bone sarcoma) were analyzed. NK effector cells were isolated from healthy donors, pre-treated with and without lenalidomide, and incubated with antibody-coated tumor cells to determine ADCC. In blocking experiments, NK cells were pre-incubated with anti-DNAM-1 or anti-NKG2D antibodies, and target colorectal cells were pre-incubated with anti-CD155 (PVR), anti-MIC-A/B, or anti-ULBP 3 antibodies. Differences between groups were assessed using unpaired and paired Student's t test and one-way ANOVA. Lenalidomide enhanced NK cell-mediated ADCC of trastuzumab- and cetuximab-coated tumor cells. Activity against colorectal cancer cells was dependent on target antigen expression, but independent of KRAS status and FcγRIIIa genotype. The extent of ADCC and its enhancement by lenalidomide correlated with NK cell expression of NKG2D and DNAM-1, and tumor cell expression of PVR and MIC-A. Blocking of NKG2D and, to a lesser extent, DNAM-1 inhibited ADCC. Anti-MIC-A/B monoclonal antibody blocked natural cytotoxicity, but not ADCC. Lenalidomide enhances the ability of IgG1-isotype antibodies to mediate ADCC of solid tumor cells, the extent of which is largely dependent on NKG2D-NKG2D ligand interactions, but appears to be independent of MIC-A/B. This provides a rationale for exploratory clinical studies and an assessment of potential biomarkers predictive of clinical benefit.
authors.affiliation: Celgene Corporation, 86 Morris Ave, Summit, NJ 07901, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.forename: Anastasia
authors.initials: A
authors.lastname: Parton
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.forename: Mary
authors.initials: M
authors.lastname: Adams
authors.forename: Peter
authors.initials: P
authors.lastname: Schafer
authors.forename: J Blake
authors.initials: JB
authors.lastname: Bartlett
mesh_terms: D019138:Antibodies, Blocking / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D058851:GPI-Linked Proteins / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000077269:Lenalidomide; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011991:Receptors, Virus / Q000276:immunology; D012509:Sarcoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D000068878:Trastuzumab; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte; D014408:Biomarkers, Tumor; D000098862:T Lineage-Specific Activation Antigen 1; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011991:Receptors, Virus; C423229:ULBP3 protein, human; C066100:poliovirus receptor; D013792:Thalidomide; D000077269:Lenalidomide; D000068878:Trastuzumab; D000068818:Cetuximab