title: Targeting of IL-2 and GM-CSF immunocytokines to a tumor vaccine leads to increased anti-tumor activity.
abstract: Fusion proteins combining antibodies with cytokines such as IL-2 and GM-CSF appear to be promising reagents for tumor therapy. In this study, we combined such immunocytokines with the tumor vaccine ATV-NDV consisting of irradiated tumor cells infected with Newcastle disease virus (NDV). The two fusion proteins bsF-GMCSF and tsHN-IL2-GM-CSF, binding, respectively, to the viral fusion protein (F) or to hemagglutinin-neuraminidase (HN) expressed on the surface of the vaccine cells and containing GM-CSF or GM-CSF and IL-2-activities were produced by recombinant antibody technology. The purified molecules showed the expected binding specificity and biological activity inherent to the respective cytokine. Using a newly established in vitro tumor neutralisation assay (TNA), we showed improved antitumoral effect through tumor growth inhibition when human peripheral blood mononuclear cells from healthy donors were stimulated with immunocytokine modified versus non-modified tumor vaccine cells. These effects induced by the fusion proteins, in the presence of a suboptimal T cell activation signal 1 provided by bsHN-CD3, occured only when these were bound to the tumor vaccine. Furthermore, it was shown that CD14+ monocytes could be activated by the GM-CSF cytokine fused within the recombinant proteins and that they contributed essentially to the antitumor effect in the TNA. The data presented here suggest an easy way for a broad clinical development and application of tumor-targeted IL-2- and GM-CSF-based immunocytokines based on the associated increase of anti-tumor activity mediated by T cells and monocytes.
authors.affiliation: German Cancer Research Center, DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. p.fournier1@yahoo.de
authors.forename: Philippe
authors.initials: P
authors.lastname: Fournier
authors.forename: Maximilian
authors.initials: M
authors.lastname: Aigner
authors.forename: Volker
authors.initials: V
authors.lastname: Schirrmacher
mesh_terms: D000818:Animals; D024201:Bystander Effect / Q000276:immunology; D016466:CHO Cells; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D023061:Gene Order; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D009522:Newcastle disease virus / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor