Dendritic cells transduced with HSV-1 amplicons expressing prostate-specific antigen generate antitumor immunity in mice.
There is currently much interest in generating cytotoxic T lymphocyte (CTL) responses against tumor antigens as a therapy for cancer. This work describes a novel gene transfer technique utilizing dendritic cells (DCs), an extremely potent form of antigen-presenting cell (APC), and herpes simplex virus-1 (HSV-1) amplicons. HSV-1 amplicons are plasmid-based viral vectors that are packaged into HSV-1 capsids, but lack viral coding sequences. Amplicon vectors have been constructed that encode the model tumor antigen ovalbumin (HSV-OVA) and human prostate-specific antigen (HSV-PSA), a protein that is expressed specifically in prostate epithelium and prostate carcinoma cells. These amplicons were packaged using a helper virus-free system that produces vector stocks that are devoid of contaminating cytotoxic helper virus. Transduction of DCs with HSV-OVA or HSV-PSA and co-culture with CTL hybridomas results in specific activation, indicating that transduced DCs express these transgenes and process the tumor antigens for class I MHC presentation to CTL. Mice immunized with HSV-PSA-transduced DCs generate a specific CTL response that can be detected in vitro by a (51)Cr-release assay and are protected from challenge with tumors that express PSA. These results indicate that DCs transduced with HSV-1 amplicon vectors may provide a tool for investigation of the biology of CTL activation by DCs and a new modality for immunotherapy of cancer.
Willis
R A
RA
Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA.
Bowers
W J
WJ
Turner
M J
MJ
Fisher
T L
TL
Abdul-Alim
C S
CS
Howard
D F
DF
Federoff
H J
HJ
Lord
E M
EM
Frelinger
J G
JG
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D019496:Cancer Vaccines; D002460:Cell Line; D002860:Chromium Radioisotopes / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D006825:Hybridomas; D007167:Immunotherapy / Q000379:methods*; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy*; D010957:Plasmids / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic
D019496:Cancer Vaccines; D002860:Chromium Radioisotopes; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D017430:Prostate-Specific Antigen