Survivin minigene DNA vaccination is effective against neuroblastoma.

The inhibitor of apoptosis protein survivin is highly expressed in neuroblastoma (NB) and survivin-specific T cells were identified in Stage 4 patients. Therefore, we generated a novel survivin minigene DNA vaccine (pUS-high) encoding exclusively for survivin-derived peptides with superior MHC class I (H2-K(k)) binding affinities and tested its efficacy to suppress tumor growth and metastases in a syngeneic NB mouse model. Vaccination was performed by oral gavage of attenuated Salmonella typhimurium SL7207 carrying pUS-high. Mice receiving the pUS-high in the prophylactic setting presented a 48-52% reduction in s.c. tumor volume, weight and liver metastasis level in contrast to empty vector controls. This response was as effective as a survivin full-length vaccine and was associated with an increased target cell lysis, increased presence of CD8(+) T-cells at the primary tumor site and enhanced production of proinflammatory cytokines by systemic CD8(+) T cells. Furthermore, depletion of CD8(+) but not CD4(+) T-cells completely abrogated the pUS-high mediated primary tumor growth suppression, demonstrating a CD8(+) T-cell mediated effect. Therapeutic vaccination with pUS-high led to complete NB eradication in over 50% of immunized mice and surviving mice showed an over 80% reduction in primary tumor growth upon rechallenge in contrast to controls. In summary, survivin-based DNA vaccination is effective against NB and the rational minigene design provides a promising approach to circumvent potentially hazardous effects of using full length antiapoptotic genes as DNA vaccines.
AuthorsStefan Fest, Nicole Huebener, Matthias Bleeke, Tahir Durmus, Alexander Stermann, Anja Woehler, Bianca Baykan, Ana C Zenclussen, Elke Michalsky, Ines S Jaeger, Robert Preissner, Oliver Hohn, Silke Weixler, Gerhard Gaedicke, Holger N Lode
JournalInternational journal of cancer. Journal international du cancer (Int J Cancer) Vol. 125 Issue 1 Pg. 104-14 (Jul 1 2009) ISSN: 1097-0215 [Electronic] United States
PMID19291796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Birc5 protein, mouse
  • Cytokines
  • Histocompatibility Antigens Class I
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Peptide Fragments
  • RNA, Messenger
  • Repressor Proteins
  • Vaccines, DNA
  • Animals
  • Apoptosis
  • CD8-Positive T-Lymphocytes (immunology)
  • Cell Line, Tumor
  • Cytokines (metabolism)
  • Cytotoxicity, Immunologic
  • Drug Design
  • Female
  • Flow Cytometry
  • Histocompatibility Antigens Class I (immunology)
  • Immunoenzyme Techniques
  • Inhibitor of Apoptosis Proteins
  • Mice
  • Mice, Inbred A
  • Microtubule-Associated Proteins (genetics)
  • Neuroblastoma (immunology, prevention & control)
  • Peptide Fragments (therapeutic use)
  • RNA, Messenger (genetics, metabolism)
  • Repressor Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vaccination
  • Vaccines, DNA (immunology)

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