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Sequential cancer immunotherapy: targeted activity of dimeric TNF and IL-8

Stefan Bauer, Nicole Adrian, Uta Siebenborn, Natalie Fadle, Margarita Plesko, Eliane Fischer, Thomas Wüest, Frank Stenner, Joachim C. Mertens, Alexander Knuth, Gerd Ritter, Lloyd J. Old and Christoph Renner
Stefan Bauer
1Oncology Department, University Hospital Zurich, Zurich, Switzerland
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Nicole Adrian
2Med. Department I, Saarland University, Homburg, Germany
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Uta Siebenborn
2Med. Department I, Saarland University, Homburg, Germany
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Natalie Fadle
2Med. Department I, Saarland University, Homburg, Germany
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Margarita Plesko
1Oncology Department, University Hospital Zurich, Zurich, Switzerland
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Eliane Fischer
1Oncology Department, University Hospital Zurich, Zurich, Switzerland
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Thomas Wüest
1Oncology Department, University Hospital Zurich, Zurich, Switzerland
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Frank Stenner
1Oncology Department, University Hospital Zurich, Zurich, Switzerland
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Joachim C. Mertens
3Medical Department, University Hospital Zurich, Zurich, Switzerland
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Alexander Knuth
1Oncology Department, University Hospital Zurich, Zurich, Switzerland
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Gerd Ritter
4Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Lloyd J. Old
4Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Christoph Renner
1Oncology Department, University Hospital Zurich, Zurich, Switzerland
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DOI:  Published January 2009
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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-872) and its N-terminally truncated form IL-83-72. 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-872 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-872 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-872 and TNF is a promising approach for cancer therapy.

This article was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.

  • Received December 22, 2008.
  • Accepted February 11, 2009.
  • Copyright © 2009 by Stefan Bauer
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Cancer Immunity Archive: 9 (1)
January 2009
Volume 9, Issue 1
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Sequential cancer immunotherapy: targeted activity of dimeric TNF and IL-8
Stefan Bauer, Nicole Adrian, Uta Siebenborn, Natalie Fadle, Margarita Plesko, Eliane Fischer, Thomas Wüest, Frank Stenner, Joachim C. Mertens, Alexander Knuth, Gerd Ritter, Lloyd J. Old and Christoph Renner
Cancer Immun January 1 2009 (9) (1) 2;

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Sequential cancer immunotherapy: targeted activity of dimeric TNF and IL-8
Stefan Bauer, Nicole Adrian, Uta Siebenborn, Natalie Fadle, Margarita Plesko, Eliane Fischer, Thomas Wüest, Frank Stenner, Joachim C. Mertens, Alexander Knuth, Gerd Ritter, Lloyd J. Old and Christoph Renner
Cancer Immun January 1 2009 (9) (1) 2;
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