Inhibition of prostate-specific membrane antigen (PSMA)-positive tumor growth by vaccination with either full-length or the C-terminal end of PSMA.
For experimental immunotherapy of prostate cancer, we used a model system to target a defined region of the extracellular domain of prostate-specific membrane antigen (PSMA). PSMA is a surface antigen expressed by prostate epithelium that is upregulated approximately 10-fold in most prostate tumors. We vaccinated BALB/c mice with NIH3T3 cells cotransfected with pST/neo plus pEF-BOS-based vectors expressing either the full-length 750-amino acid human PSMA or only the C-terminal 180-amino acid region (PSMc). PSMc lies C-terminal to the transferrin receptor-like sequence in the extracellular domain of PSMA. BALB/c mice were injected i.p. 4 times at weekly intervals with vaccine cells. Vaccinated mice were then challenged s.c. with Renca/PSMA, a BALB/c renal cell carcinoma line transfected to express human PSMA. Growth of Renca/PSMA tumors was substantially retarded and host survival significantly prolonged in mice prevaccinated with either 3T3/PSMA or 3T3/PSMc. Furthermore, antiserum from vaccinated mice intensely immunocytochemically stained LNCaP, a PSMA-positive human prostate cancer cell line. In contrast, control mice similarly prevaccinated i.p. with 3T3/neo (NIH3T3 cells transfected with pST/neo alone) developed Renca/PSMA tumors, which were palpable within 2 weeks and lethal by 5 weeks. Serum from 3T3/neo-vaccinated mice did not immunocytochemically stain LNCaP cells. The antitumor activity induced by vaccination with 3T3/PSMc was also demonstrated via growth inhibition of established LNCaP tumors xenografted in athymic mice following passive transfer of immune serum from vaccinated mice. Our results suggest that vaccination with PSMc induces adaptive humoral activity, which is directed against the extracellular region of human PSMA and can significantly inhibit human prostate cancer growth in athymic mice, and that administration of antibodies to PSMA may provide a passive treatment modality for immunocompromised patients.
Kuratsukuri
Katsuyuki
K
Department of Urology, Upstate Medical University, State University of New York, 750 East Adams Street, Syracuse, NY 13210, USA.
Sone
Tomomichi
T
Wang
Ching Y
CY
Nishisaka
Nobuyasu
N
Jones
Richard F
RF
Haas
Gabriel P
GP
D016475:3T3 Cells; D000818:Animals; D000954:Antigens, Surface; D019496:Cancer Vaccines; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000737:chemistry; D002470:Cell Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D043425:Glutamate Carboxypeptidase II; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000954:Antigens, Surface; D019496:Cancer Vaccines; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II