Intravenous genetic mesothelin vaccine based on human adenovirus 40 inhibits growth and metastasis of pancreatic cancer.
Int J Cancer
; 133(1): 88-97, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23233329
ABSTRACT
High pancreatic cancer mortality and poor prognosis are caused by the difficulty for early diagnosis and extremely low rates of resection because of metastasis. Mesothelin overexpression in pancreatic cancer is a remarkable biomarker for tumor progression, especially for invasion and metastasis. Here, we generated a novel replication-defective recombinant adenovirus 40 (rAd40), whose gene delivery properties are totally different from a conventional rAd5. In this study, we have identified intravenous administration with rAd40 expressing mouse mesothelin (Msln) as an effective prophylactic cancer vaccine against metastatic lesions of pancreatic cancer in mice. Intravenous administration of rAd40 (rAd40 i.v.) achieved transgene delivery in wider range of organs compared to rAd5 i.v., while rAd5 was distributed mainly to the liver, spleen, and lungs. Additionally, rAd40 i.v. showed less transduction of the liver or inflammatory responses, resulted in reduced liver toxicity compared to rAd5 i.v. Also, more robust systemic antigen-specific immune responses were stimulated by rAd40 i.v. Pretreatment with a single ovalbumin-expressing rAd40 i.v. prevented tumor growth in mouse subcutaneous models of ovalbumin-expressing pancreatic cancer. When used with Msln-expressing rAd40 i.v., Msln protein expression and metastases were suppressed in a syngeneic orthotopic mouse model of pancreatic cancer, corresponding to the detection of Msln- and tumor-specific cytotoxic T lymphocyte (CTL). Our novel methods generated antitumor effects against antigen-expressing tumors through antigen- and tumor-specific CTL-mediated immunity. Thus, our results indicate that a rAd40-based intravenous vaccine provides a new strategy for the effective control of metastatic pancreatic cancer and novel therapy against other cancers and infectious diseases.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Problema de saúde:
6_endocrine_disorders
/
6_pancreatic_cancer
Assunto principal:
Neoplasias Pancreáticas
/
Adenovírus Humanos
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Vacinas Anticâncer
/
Proteínas Ligadas por GPI
Tipo de estudo:
Prognostic_studies
/
Screening_studies
Limite:
Animals
Idioma:
En
Revista:
Int J Cancer
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos