RESUMEN

Human prostate tumor vaccine and gene therapy trials using ex vivo methods to prime dendritic cells (DCs) with prostate specific membrane antigen (PSMA) have been somewhat successful, but to date the lengthy ex vivo manipulation of DCs has limited the widespread clinical utility of this approach. Our goal was to improve upon cancer vaccination with tumor antigens by delivering PSMA via a CD40-targeted adenovirus vector directly to DCs as an efficient means for activation and antigen presentation to T-cells. To test this approach, we developed a mouse model of prostate cancer by generating clonal derivatives of the mouse RM-1 prostate cancer cell line expressing human PSMA (RM-1-PSMA cells). To maximize antigen presentation in target cells, both MHC class I and TAP protein expression was induced in RM-1 cells by transduction with an Ad vector expressing interferon-gamma (Ad5-IFNγ). Administering DCs infected ex vivo with CD40-targeted Ad5-huPSMA, as well as direct intraperitoneal injection of the vector, resulted in high levels of tumor-specific CTL responses against RM-1-PSMA cells pretreated with Ad5-IFNγ as target cells. CD40 targeting significantly improved the therapeutic antitumor efficacy of Ad5-huPSMA encoding PSMA when combined with Ad5-IFNγ in the RM-1-PSMA model. These results suggest that a CD-targeted adenovirus delivering PSMA may be effective clinically for prostate cancer immunotherapy.

Asunto(s)

Adenoviridae/genética , Antígenos de Superficie/genética , Antígenos CD40/metabolismo , Células Dendríticas/inmunología , Vectores Genéticos/genética , Glutamato Carboxipeptidasa II/genética , Neoplasias de la Próstata/prevención & control , Vacunación/métodos , Transportador de Casetes de Unión a ATP, Subfamilia B, Miembro 2 , Miembro 3 de la Subfamilia B de Transportadores de Casetes de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Adyuvantes Inmunológicos/metabolismo , Animales , Presentación de Antígeno/genética , Presentación de Antígeno/inmunología , Antígenos de Superficie/metabolismo , Antígenos CD40/inmunología , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/virología , Glutamato Carboxipeptidasa II/metabolismo , Antígenos HLA-A/genética , Humanos , Interferón gamma/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Terapia Molecular Dirigida , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Citotóxicos/virología