Safety and immunological efficacy of a prostate cancer plasmid DNA vaccine encoding prostatic acid phosphatase (PAP).
Prostatic acid phosphatase (PAP) is a prostate tumor antigen currently being investigated as a target antigen in several human vaccine trials, some with evidence of clinical benefit. We have previously demonstrated that plasmid DNA vaccines encoding either human or rat PAP can elicit antigen-specific cellular and humoral immunity in rat models. The current study was performed to determine the safety and potential immunological efficacy in rodents of large and repetitive doses of a GMP-grade plasmid DNA vaccine encoding human PAP, pTVG-HP. Fifty-four male Lewis rats were immunized intradermally at 2-week intervals with 100, 500, or 1,500 microg pTVG-HP with 5 microg recombinant rat GM-CSF protein given as a vaccine adjuvant. An additional 12 male Lewis rats served as controls with groups immunized with 1,500 microg of a parental DNA vector not encoding human PAP, and a group that received GM-CSF protein only without plasmid DNA. Groups of animals (n=3-6) were euthanized after two, four, or six immunizations with collections of tissues and blood for toxicity assessment and immunological analysis. No significant toxicities were observed in terms of animal weights, histopathology, hematological changes, or changes in serum chemistries. Six of fifty-four were found to have subtle evidence of possible renal toxicity, however these findings were not statistically different from control animals. The vaccine was found to be effective in eliciting PAP-specific CD4 and CD8 T cells, predominantly Th1 in type, in all immunized animals at all doses and numbers of immunizations. PAP-specific IgG were detected in a dose-dependent fashion, with titers increasing after multiple immunizations. These studies demonstrate that, in rats, immunization with the pTVG-HP vaccine is safe and effective in eliciting PAP-specific cellular and humoral immune responses. These findings support the further clinical evaluation of pTVG-HP in patients with prostate cancer.
Johnson
Laura E
LE
Department of Medicine, Section of Medical Oncology, University of Wisconsin-Madison, K4/518 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA.
Frye
Thomas P
TP
Arnot
Alana R
AR
Marquette
Carrie
C
Couture
Larry A
LA
Gendron-Fitzpatrick
Annette
A
McNeel
Douglas G
DG
D000135:Acid Phosphatase / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology* / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D007111:Immunity, Cellular / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D010957:Plasmids / Q000276:immunology; D011467:Prostate / Q000201:enzymology* / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000009:adverse effects / Q000276:immunology / Q000633:toxicity
D019496:Cancer Vaccines; D007074:Immunoglobulin G; D019444:Vaccines, DNA; D000135:Acid Phosphatase