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Survivin minigene DNA vaccination is effective against neuroblastoma
Author(s) -
Fest Stefan,
Huebener Nicole,
Bleeke Matthias,
Durmus Tahir,
Stermann Alexander,
Woehler Anja,
Baykan Bianca,
Zenclussen Ana C.,
Michalsky Elke,
Jaeger Ines S.,
Preissner Robert,
Hohn Oliver,
Weixler Silke,
Gaedicke Gerhard,
Lode Holger N.
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24291
Subject(s) - survivin , dna vaccination , cancer research , cd8 , minigene , immunotherapy , biology , immunology , immune system , cancer , gene , immunization , rna , biochemistry , rna splicing , genetics
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. © 2009 UICC