title: Recombinant interleukin-2 significantly augments activity of rituximab in human tumor xenograft models of B-cell non-Hodgkin lymphoma.
abstract: Recombinant interleukin-2 (rIL-2) is a pleiotropic cytokine that activates select immune effector cell responses associated with antitumor activity, including antibody-dependent cellular cytotoxicity (ADCC). Rituximab is an anti-CD20 monoclonal antibody that activates ADCC in non-Hodgkin lymphoma (NHL). The ability of rIL-2 to augment rituximab-dependent tumor responses was investigated. The efficacy of rIL-2 in combination with rituximab was evaluated in 2 NHL tumor xenograft models: the CD20hi, rituximab-sensitive, low-grade Daudi model and the CD20lo, aggressive, rituximab-resistant Namalwa model. Combination of rIL-2 plus rituximab was synergistic in a rituximab-sensitive Daudi tumor model, as evidenced by significant tumor regressions and increased time to tumor progression, compared with rIL-2 and rituximab single agents. In contrast, rituximab-resistant Namalwa tumors were responsive to single-agent rIL-2 and showed an increased response when combined with rituximab. Using in vitro killing assays, rIL-2 was shown to enhance activity of rituximab by activating ADCC and lymphokine-activated killer activity. Additionally, the activity of rIL-2 plus rituximab F(ab')2 was similar to that of rIL-2 alone, indicating a critical role for immunoglobulin G1 Fc-FcgammaR-effector responses in mediating ADCC. Antiproliferative and apoptotic tumor responses, along with an influx of immune effector cells, were observed by immunohistochemistry. Collectively, the data suggest that rIL-2 mediates potent tumoricidal activity against NHL tumors, in part, through activation and trafficking of monocytes and natural killer cells to tumors. These data support the mechanistic and therapeutic rationale for combination of rIL-2 with rituximab in NHL clinical trials and for single-agent rIL-2 in rituximab-resistant NHL patients.
authors.affiliation: Chiron Corporation, Biopharma Research and Development, Emeryville, CA 94608, USA. Daniel_Menezes@chiron.com
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Lopes de Menezes
authors.forename: Kimberly
authors.initials: K
authors.lastname: Denis-Mize
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.forename: Helen
authors.initials: H
authors.lastname: Ye
authors.forename: John C
authors.initials: JC
authors.lastname: Kunich
authors.forename: Evelyn N
authors.initials: EN
authors.lastname: Garrett
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Cousens
authors.forename: Arnold B
authors.initials: AB
authors.lastname: Gelb
authors.forename: Carla
authors.initials: C
authors.lastname: Heise
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wilson
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Aukerman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009000:Monocytes / Q000276:immunology; D000069283:Rituximab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D007141:Immunoglobulin Fc Fragments; D007376:Interleukin-2; D000069283:Rituximab