A Bicistronic Adenoviral Vector Carrying Cytosine Deaminase and Granulocyte-Macrophage Colony-Stimulating Factor Increases the Therapeutic Efficacy of Cancer Gene Therapy.

Akbulut, Hakan; Coleri, Arzu; Sahin, Gunce; Tang, Yucheng; Icli, Fikri

Akbulut, Hakan; Coleri, Arzu; Sahin, Gunce; Tang, Yucheng; Icli, Fikri.

Afiliación

Akbulut H; 1Deparment of Basic Oncology, Ankara University Cancer Research Institute, Ankara, Turkey.
Coleri A; 2Deparment of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey.
Sahin G; 3Department of Biology, Ankara University Faculty of Science, Ankara, Turkey.
Tang Y; 4Deparment of Biology, Izzet Baysal University Faculty of Science, Bolu, Turkey.
Icli F; 5MicroVAx LLCi, Manassas, Virginia.

Hum Gene Ther ; 30(8): 999-1007, 2019 08.

Article en En | MEDLINE | ID: mdl-30892086

RESUMEN

The combination of cytotoxic treatment modalities, including oncolytic viral gene therapies and immunotherapy, usually yields a synergistic effect. In the current study, a bicistronic adenoviral vector, Ad-CD-GMCSF, carrying the cytosine deaminase (CD) and granulocyte-macrophage colony-stimulating factor (GM-CSF) transcription units driven by a cytomegalovirus promoter was constructed, and the in vitro efficacy of the vector was tested in tumor cell lines and a syngeneic mouse model of colon cancer. The tumor cells infected with Ad-CD-GMCSF vector were found to produce a substantial amount of GM-CSF in tumor cell lines. Accordingly, the vector carrying CD and GM-CSF transcription units together induced a potent antitumor immunity with a significantly increased number of tumor-specific T cells and tumor-specific T-cell cytotoxicity (p < 0.001). The tumor growth rate of Ad-CD-GMCSF-treated mice was significantly lower when compared to the control and an adenoviral vector carrying only the CD transcription unit (Ad-CD; p < 0.05). Likewise, the median overall survival of the Ad-CD-GMCSF vector group was significantly higher than that of the control and Ad-CD groups (34.0 ± 12.8 vs. 14.0 ± 0.5 and 23.0 ± 2.8 days, respectively; p < 0.001). In conclusion, along with its cytotoxic effect, the high immunostimulatory effect of the bicistronic Ad-CD-GMCSF vector has excellent potential in the treatment of cancers.

Asunto(s)

Adenoviridae/genética; Citosina Desaminasa/genética; Terapia Genética; Vectores Genéticos/genética; Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética; Neoplasias/genética; Neoplasias/terapia; Transgenes; Animales; Citocinas/metabolismo; Citosina Desaminasa/metabolismo; Citotoxicidad Inmunológica; Modelos Animales de Enfermedad; Expresión Génica; Orden Génico; Terapia Genética/métodos; Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo; Humanos; Inmunomodulación; Ratones; Neoplasias/inmunología; Neoplasias/patología; Resultado del Tratamiento; Microambiente Tumoral; Ensayos Antitumor por Modelo de Xenoinjerto

Palabras clave

5-fluorouracil; GM-CSF; adenoviral vector; cytosine deaminase; gene therapy

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Terapia Genética / Adenoviridae / Factor Estimulante de Colonias de Granulocitos y Macrófagos / Transgenes / Citosina Desaminasa / Vectores Genéticos / Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Hum Gene Ther Asunto de la revista: GENETICA MEDICA / TERAPEUTICA Año: 2019 Tipo del documento: Article País de afiliación: Turquía Pais de publicación: Estados Unidos

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google