Dendritic cell based PSMA immunotherapy for prostate cancer using a CD40-targeted adenovirus vector

• Published in: PloS one Vol. 7; no. 10; p. e46981
• Main Authors: Williams, Briana Jill, Bhatia, Shilpa, Adams, Lisa K, Boling, Susan, Carroll, Jennifer L, Li, Xiao-Lin, Rogers, Donna L, Korokhov, Nikolay, Kovesdi, Imre, Pereboev, Alexander V, Curiel, David T, Mathis, J Michael
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.10.2012; Public Library of Science (PLoS)
• Subjects: Adenoviridae - genetics; Adenoviruses; Adjuvants, Immunologic - metabolism; Analysis; Animals; Anticancer properties; Antigen (tumor-associated); Antigen presentation; Antigen Presentation - genetics; Antigen Presentation - immunology; Antigens; Antigens, Surface - genetics; Antigens, Surface - metabolism; Antitumor activity; ATP Binding Cassette Transporter, Subfamily B, Member 2; ATP Binding Cassette Transporter, Subfamily B, Member 3; ATP-Binding Cassette Transporters - genetics; Biochemistry; Biological response modifiers; Biology; Cancer; Cancer immunotherapy; Cancer therapies; Cancer treatment; Cancer vaccines; Cancer Vaccines - genetics; Cancer Vaccines - immunology; CD40 antigen; CD40 Antigens - immunology; CD40 Antigens - metabolism; Cell Line, Tumor; Cell Survival - genetics; Cell Survival - immunology; Cellular biology; Clinical trials; Cloning; Cytotoxicity; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - virology; Drug therapy; Gene expression; Gene therapy; Genetic Vectors - genetics; Glutamate Carboxypeptidase II - genetics; Glutamate Carboxypeptidase II - metabolism; Health aspects; Health sciences; HLA-A Antigens - genetics; Humans; Immunotherapy; Interferon; Interferon-gamma - genetics; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - virology; Laboratory animals; Ligands; Lymphatic system; Lymphocytes T; Major histocompatibility complex; Male; Medicine; Melanoma; Mice; Mice, Inbred C57BL; Molecular biology; Molecular Targeted Therapy; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - immunology; Prostatic Neoplasms - prevention & control; T cells; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; T-Lymphocytes, Cytotoxic - virology; TAP protein; Tumor antigens; Urology; Vaccination; Vaccination - methods; Vectors (Biology); γ-Interferon; Louisiana; Alabama; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0046981

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.