Cancer Immunology, Immunotherapy

, Volume 61, Issue 9, pp 1473–1484

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

  • Ute E. Burkhardt
  • Arjen Sloots
  • Vera Jakobi
  • Wei-Zen Wei
  • Federica Cavallo
  • Björn-Philipp Kloke
  • Winfried S. Wels
Original article

DOI: 10.1007/s00262-012-1215-7

Cite this article as:
Burkhardt, U.E., Sloots, A., Jakobi, V. et al. Cancer Immunol Immunother (2012) 61: 1473. doi:10.1007/s00262-012-1215-7

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.

Keywords

Cancer vaccineErbB2/HER2ErbB2-transgenic miceIL-15CTLA-4

Supplementary material

262_2012_1215_MOESM1_ESM.pdf (632 kb)
Supplementary material 1 (PDF 632 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ute E. Burkhardt
    • 1
  • Arjen Sloots
    • 1
  • Vera Jakobi
    • 1
  • Wei-Zen Wei
    • 2
  • Federica Cavallo
    • 3
  • Björn-Philipp Kloke
    • 1
  • Winfried S. Wels
    • 1
  1. 1.Chemotherapeutisches Forschungsinstitut Georg-Speyer-HausFrankfurt am MainGermany
  2. 2.Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  3. 3.Department of Clinical and Biological Sciences, Molecular Biotechnology CenterUniversity of TurinTurinItaly