Survivin minigene DNA vaccination is effective against neuroblastoma.

Abstract

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.

• Authors: Stefan 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
• Journal: International journal of cancer (Int J Cancer) Vol. 125 Issue 1 Pg. 104-14 (Jul 01 2009) ISSN: 1097-0215 [Electronic] United States
• PMID: 19291796 (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
• Survivin
• Vaccines, DNA

Topics

• 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
• Survivin
• Vaccination
• Vaccines, DNA (immunology)