Efficient transfer of PSA and PSMA cDNAs into DCs generates antibody and T cell antitumor responses in vivo.
Gene therapy for prostate cancer may be realized through transduction of whole genes, such as PSA or PSMA, into immunotherapeutic dendritic cells (DCs). An oncoretroviral vector encoding human PSMA and a bicistronic oncoretroviral vector encoding human PSA and cell surface CD25 cDNAs were constructed. Remarkably, transfer of PSA/CD25 or PSMA cDNA during murine hematopoietic cell differentiation into DCs occurred with approximately 80% efficiency. In vitro, transduced DCs retained allostimulatory function and primed syngeneic T cells for tumor antigen-specific IFN-gamma secretion. In test experiments designed to elucidate mechanisms in vivo, syngeneic recipients of transduced DCs had increased anti-human PSA antibody titers and tumor-specific CD8(+) T cell IFN-gamma secretion with no detectable immune response to CD25. Gene-modified DC recipients had increased protection from specific tumor challenge for at least 18 weeks post-vaccination. DC vaccination also protected both male and female recipients. Gene-modified DC vaccination mediated regression of established, specific gene-expressing, TRAMP-C1 prostate cancer cell tumors. These findings indicate that antibody and cellular responses generated through PSA and PSMA gene transfer into DC yielded protective immunity, thereby providing further preclinical support for the implementation of immuno-gene therapy approaches for prostate cancer.
Medin
Jeffrey A
JA
Division of Experimental Therapeutics, Ontario Cancer Institute, Toronto, Ontario, Canada M5G 2M1. jmedin@uhnres.utoronto.ca
Liang
Sheng-Ben
SB
Hou
Jeannie Whit-Shan
JW
Kelley
Leslie S
LS
Peace
David J
DJ
Fowler
Daniel H
DH
D000818:Animals; D000912:Antibodies, Neoplasm / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D018076:DNA, Complementary / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D043425:Glutamate Carboxypeptidase II / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D017430:Prostate-Specific Antigen / Q000235:genetics* / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000276:immunology
D000912:Antibodies, Neoplasm; D000954:Antigens, Surface; D019496:Cancer Vaccines; D018076:DNA, Complementary; D015375:Receptors, Interleukin-2; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen