title: Sequential cancer immunotherapy: targeted activity of dimeric TNF and IL-8.
abstract: Polymorphonuclear neutrophils (PMNs) are potent effectors of inflammation and their attempts to respond to cancer are suggested by their systemic, regional and intratumoral activation. We previously reported on the recruitment of CD11b+ leukocytes due to tumor site-specific enrichment of TNF activity after intravenous administration of a dimeric TNF immunokine with specificity for fibroblast activation protein (FAP). However, TNF-induced chemo-attraction and extravasation of PMNs from blood into the tumor is a multistep process essentially mediated by interleukin 8. With the aim to amplify the TNF-induced and IL-8-mediated chemotactic response, we generated immunocytokines by N-terminal fusion of a human anti-FAP scFv fragment with human IL-8 (IL-8(72)) and its N-terminally truncated form IL-8(3-72). Due to the dramatic difference in chemotaxis induction in vitro, we favored the mature chemokine fused to the anti-FAP scFv for further investigation in vivo. BALB/c nu/nu mice were simultaneously xenografted with FAP-positive or -negative tumors and extended chemo-attraction of PMNs was only detectable in FAP-expressing tissue after intravenous administration of the anti-FAP scFv-IL-8(72) construct. As TNF-activated PMNs are likewise producers and primary targets for IL-8, we investigated the therapeutic efficacy of co-administration of both effectors: Sequential application of scFv-IL-8(72) and dimeric IgG1-TNF fusion proteins significantly enhanced anti-tumor activity when compared either to a single effector treatment regimen or sequential application of non-targeted cytokines, indicating that the tumor-restricted sequential application of IL-8(72) and TNF is a promising approach for cancer therapy.
authors.affiliation: Oncology Department, University Hospital Zurich, Zurich, Switzerland. stefan1.bauer@med.uni-heidelberg.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Nicole
authors.initials: N
authors.lastname: Adrian
authors.forename: Uta
authors.initials: U
authors.lastname: Siebenborn
authors.forename: Natalie
authors.initials: N
authors.lastname: Fadle
authors.forename: Margarita
authors.initials: M
authors.lastname: Plesko
authors.forename: Eliane
authors.initials: E
authors.lastname: Fischer
authors.forename: Thomas
authors.initials: T
authors.lastname: Wüest
authors.forename: Frank
authors.initials: F
authors.lastname: Stenner
authors.forename: Joachim C
authors.initials: JC
authors.lastname: Mertens
authors.forename: Alexander
authors.initials: A
authors.lastname: Knuth
authors.forename: Gerd
authors.initials: G
authors.lastname: Ritter
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Christoph
authors.initials: C
authors.lastname: Renner
mesh_terms: D000818:Animals; D000941:Antigens; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D010450:Endopeptidases; D018093:Gelatinases; D006801:Humans; D007167:Immunotherapy; D016209:Interleukin-8 / Q000494:pharmacology / Q000627:therapeutic use*; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D055503:Protein Multimerization / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012697:Serine Endopeptidases / Q000378:metabolism; D014162:Transfection; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000941:Antigens; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D016209:Interleukin-8; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D012697:Serine Endopeptidases; D014409:Tumor Necrosis Factor-alpha; D000099167:Fibroblast Activation Protein Alpha