Dendritic cell based PSMA immunotherapy for prostate cancer using a CD40-targeted adenovirus vector.
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.
Gene Therapy Program, Department of Urology, LSU Health Sciences Center, Shreveport, Louisiana, United States of America.
Briana Jill
BJ
Williams
Shilpa
S
Bhatia
Lisa K
LK
Adams
Susan
S
Boling
Jennifer L
JL
Carroll
Xiao-Lin
XL
Li
Donna L
DL
Rogers
Nikolay
N
Korokhov
Imre
I
Kovesdi
Alexander V
AV
Pereboev
David T
DT
Curiel
J Michael
JM
Mathis
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics*; D000276:Adjuvants, Immunologic / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000954:Antigens, Surface / Q000235:genetics* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005822:Genetic Vectors / Q000235:genetics*; D043425:Glutamate Carboxypeptidase II / Q000235:genetics* / Q000378:metabolism; D015234:HLA-A Antigens / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014611:Vaccination / Q000379:methods*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000276:Adjuvants, Immunologic; D000954:Antigens, Surface; D019013:CD40 Antigens; D019496:Cancer Vaccines; D015234:HLA-A Antigens; C486171:Tap1 protein, mouse; C489516:Tap2 protein, mouse; D007371:Interferon-gamma; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II