title: Follicular lymphoma: in vitro effects of combining lymphokine-activated killer (LAK) cell-induced cytotoxicity and rituximab- and obinutuzumab-dependent cellular cytotoxicity (ADCC) activity.
abstract: Follicular lymphoma (FL) is a disease of paradoxes-incurable but with a long natural history. We hypothesized that a combination of lymphokine-activated killer (LAK) cells and monoclonal antibodies might provide a robust synergistic treatment and tested this hypothesis in a phase II clinical trial (NCT01329354). In this trial, in addition to R-CHOP, we alternated the administration of only rituximab with rituximab and autologous LAK cells that were expanded ex vivo. Our objective was to determine the in vitro capability of LAK cells generated from FL patients to produce cytotoxicity against tumor cell lines and to determine rituximab- and obinutuzumab-induced cytotoxicity via antibody-dependent cellular cytotoxicity (ADCC) activity. We analyzed the LAK cell-induced cytotoxicity and rituximab (R)- and obinutuzumab (GA101)-induced ADCC activity. We show that LAK cells generated from FL patients induce cytotoxicity against tumor cell lines. R and GA101 enhance cytolysis through ADCC activity of LAK cells. Impaired LAK cell cytotoxicity and ADCC activity were detected in 50 % of patients. Percentage of NK cells in LAK infusions were correlated with the R- and GA101-induced ADCC. Our results indicate that the combination of R or GA101 and LAK cells should be an option as frontline maintenance therapy in patients with FL.
authors.affiliation: Department of Hematology, San Pedro Hospital, Logroño, La Rioja, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: García-Muñoz
authors.affiliation: Department of Hematology, University Clinic of Navarre, Pamplona, Navarra, Spain.|Lymphoproliferative Group, Health Research Institute Navarra (IDISNA), Pamplona, Navarra, Spain.
authors.forename: Ascensión
authors.initials: A
authors.lastname: López-Díaz-de-Cerio
authors.affiliation: Department of Hematology, San Pedro Hospital, Logroño, La Rioja, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Feliu
authors.affiliation: Lymphoproliferative Group, Health Research Institute Navarra (IDISNA), Pamplona, Navarra, Spain.|Department of Pathology, Hospital Complex Navarre, Pamplona, Navarra, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Panizo
authors.affiliation: Translational Research Unit, Health Research Institute Aragón, CIBER Rare Diseases, CIBERER, Zaragoza, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Giraldo
authors.affiliation: Lymphoproliferative Group, Health Research Institute Navarra (IDISNA), Pamplona, Navarra, Spain.|Department of Hematology, Hospital Complex Navarre, Pamplona, Navarra, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rodríguez-Calvillo
authors.affiliation: Department of Hematology, University Hospital, 12 de Octubre, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Grande
authors.affiliation: Lymphoproliferative Group, Health Research Institute Navarra (IDISNA), Pamplona, Navarra, Spain.|Department of Hematology, Hospital Complex Navarre, Pamplona, Navarra, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Pena
authors.affiliation: Department of Hematology, University Clinic Lozano Blesa, Zaragoza, Aragón, Spain.
authors.forename: Mayte
authors.initials: M
authors.lastname: Olave
authors.affiliation: Department of Hematology, University Clinic of Navarre, Pamplona, Navarra, Spain. cpanizo@unav.es.|Lymphoproliferative Group, Health Research Institute Navarra (IDISNA), Pamplona, Navarra, Spain. cpanizo@unav.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Panizo
authors.affiliation: Department of Hematology, University Clinic of Navarre, Pamplona, Navarra, Spain.|Lymphoproliferative Group, Health Research Institute Navarra (IDISNA), Pamplona, Navarra, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Inogés
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006801:Humans; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology* / Q000378:metabolism; D018655:Lymphocyte Count; D008224:Lymphoma, Follicular / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D000069283:Rituximab / Q000276:immunology* / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000069283:Rituximab; C543332:obinutuzumab
keywords: Antibody-dependent cellular cytotoxicity (ADCC); Follicular lymphoma (FL); Lymphokine-activated killer (LAK) cells; Natural killer cells (NK); Obinutuzumab (GA101); Rituximab (R)