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IL-15 augments antitumoral activity of an ErbB2/HER2 cancer vaccine targeted to professional antigen-presenting cells

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Abstract

Targeted delivery of tumor-associated antigens to professional antigen-presenting cells (APC) is being explored as a strategy to enhance the antitumoral activity of cancer vaccines. Here, we generated a cell-based system for continuous in vivo production of a CTLA-4-ErbB2 fusion protein as a therapeutic vaccine. The chimeric CTLA-4-ErbB2 molecule contains the extracellular domain of CTLA-4 for specific targeting to costimulatory B7 molecules on the surface of APC, genetically fused to residues 1–222 of human ErbB2 (HER2) as an antigenic determinant. In wild-type BALB/c mice, inoculation of syngeneic epithelial cells continuously secreting the CTLA-4-ErbB2 fusion vaccine in the vicinity of subcutaneously growing ErbB2-expressing renal cell carcinomas resulted in the rejection of established tumors, accompanied by the induction of ErbB2-specific antibodies and cytotoxic T cells. In contrast, treatment with CTLA-4-ErbB2 vaccine-secreting producer cells alone was insufficient to induce tumor rejection in ErbB2-transgenic WAP-Her-2 F1 mice, which are characterized by pronounced immunological tolerance to the human self-antigen. When CTLA-4-ErbB2 producer cells were modified to additionally secrete interleukin (IL)-15, antigen-specific antitumoral activity of the vaccine in WAP-Her-2 F1 mice was restored, documented by an increase in survival, and marked inhibition of the growth of established ErbB2-expressing, but not antigen-negative tumors. Our results demonstrate that continuous in vivo expression of an APC-targeted ErbB2 fusion protein results in antigen-specific immune responses and antitumoral activity in tumor-bearing hosts, which is augmented by the pleiotropic cytokine IL-15. This provides a rationale for further development of this approach for specific cancer immunotherapy.

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Acknowledgments

This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (DFG) GRK1172 and the LOEWE-Schwerpunkt Onkogene Signaltransduktion Frankfurt (OSF). We thank Dr. Christiane Sahm, Georg-Speyer-Haus, for lentiviral transfer vector pS-IL15-IEW; Dr. Giulio C. Spagnoli, University of Basel, for NY-ESO-1-specific mAb D8.38; Dr. Cristina Mastini, University of Turin for help with the set-up of WAP-Her-2 mice, the staff of the Georg-Speyer-Haus animal facility, for maintaining the transgenic mouse colony; Dr. Kurt Schönfeld, Georg-Speyer-Haus, for helpful suggestions and establishment of depletion experiments; and Mrs. Annemarie Schimpf, Mrs. Barbara Uherek, and Mr. Thorsten Geyer, Georg-Speyer-Haus, for excellent technical assistance.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Ehrlich-Straße 42-44, 60596, Frankfurt am Main, Germany

    Ute E. Burkhardt, Arjen Sloots, Vera Jakobi, Björn-Philipp Kloke & Winfried S. Wels

  2. Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201, USA

    Wei-Zen Wei

  3. Department of Clinical and Biological Sciences, Molecular Biotechnology Center, University of Turin, 10126, Turin, Italy

    Federica Cavallo

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  1. Ute E. Burkhardt
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  2. Arjen Sloots
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  3. Vera Jakobi
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  4. Wei-Zen Wei
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  5. Federica Cavallo
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  6. Björn-Philipp Kloke
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  7. Winfried S. Wels
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Correspondence to Winfried S. Wels.

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Burkhardt, U.E., Sloots, A., Jakobi, V. et al. IL-15 augments antitumoral activity of an ErbB2/HER2 cancer vaccine targeted to professional antigen-presenting cells. Cancer Immunol Immunother 61, 1473–1484 (2012). https://doi.org/10.1007/s00262-012-1215-7

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