Sequential cancer immunotherapy: Targeted activity of dimeric TNF and IL-8 Journal Article
| Authors: | Bauer, S.; Adrian, N.; Siebenborn, U.; Fadle, N.; Plesko, M.; Fischer, E.; Wüest, T.; Stenner, F.; Mertens, J. C.; Knuth, A.; Ritter, G.; Old, L. J.; Renner, C. |
| Article 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 chemoattraction 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 <sub>72</sub>) and its N-terminally truncated form IL-8<sub>3-72</sub>. 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<sub>72</sub> 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<sub>72</sub> 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<sub>72</sub> and TNF is a promising approach for cancer therapy. Copyright © 2009 by Stefan Bauer. |
| Keywords: | controlled study; treatment outcome; unclassified drug; human cell; drug efficacy; drug potentiation; nonhuman; antineoplastic agent; neoplasm; neoplasms; mouse; animal; metabolism; animals; mice; animal tissue; cancer immunotherapy; interleukin 8; tumor markers, biological; animal experiment; animal model; in vivo study; antineoplastic activity; in vitro study; drug effect; drug screening; xenograft model antitumor assays; transfection; tumor antigen; tumor marker; immunology; anti-fap scfv; il-8; polymorphonuclear neutrophils; recombinant fusion protein; tnf; chemokine; immunoglobulin fragment; immunoglobulin g1 antibody recombinant interleukin 8 fusion protein; immunoglobulin g1 antibody tumor necrosis factor fusion protein; seprase; antigen; fap protein, human; hybrid protein; serine proteinase; tumor necrosis factor alpha; amino terminal sequence; bagg albino mouse; cell strain hek293; chemotaxis; fibrosarcoma; human cell culture; neutrophil; genetic transfection; immunotherapy; kinetics; mononuclear cell; protein multimerization; antigens; antigens, neoplasm; interleukin-8; leukocytes, mononuclear; recombinant fusion proteins; serine endopeptidases; tumor necrosis factor-alpha |
| Journal Title: | Cancer Immunity |
| Volume: | 9 |
| ISSN: | 1424-9634 |
| Publisher: | Academy of Cancer Immunology |
| Date Published: | 2009-01-19 |
| Start Page: | 2 |
| Language: | English |
| PUBMED: | 19267427 |
| PROVIDER: | scopus |
| PMCID: | PMC2935764 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 30 November 2010" - "Art. No.: A2" - "Source: Scopus" |
