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.
Fest
Stefan
S
Pediatrics, Experimental Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Huebener
Nicole
N
Bleeke
Matthias
M
Durmus
Tahir
T
Stermann
Alexander
A
Woehler
Anja
A
Baykan
Bianca
B
Zenclussen
Ana C
AC
Michalsky
Elke
E
Jaeger
Ines S
IS
Preissner
Robert
R
Hohn
Oliver
O
Weixler
Silke
S
Gaedicke
Gerhard
G
Lode
Holger N
HN
D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D015195:Drug Design; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008805:Mice, Inbred A; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009447:Neuroblastoma / Q000276:immunology / Q000517:prevention & control*; D010446:Peptide Fragments / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*
C117749:Birc5 protein, mouse; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D012097:Repressor Proteins; D000077022:Survivin; D019444:Vaccines, DNA