A novel alphavirus vaccine encoding prostate-specific membrane antigen elicits potent cellular and humoral immune responses.
OBJECTIVE
Prostate-specific membrane antigen (PSMA) is an attractive target for active immunotherapy. Alphavirus vaccines have shown promise in eliciting immunity to tumor antigens. This study investigated the immunogenicity of alphavirus vaccine replicon particles (VRP) that encode PSMA (PSMA-VRP).


METHODS
Cells were infected with PSMA-VRP and evaluated for PSMA expression and folate hydrolase activity. Mice were immunized s.c. with PSMA-VRP or purified PSMA protein. Sera, splenocytes, and purified T cells were evaluated for the magnitude, durability, and epitope specificity of the anti-PSMA response. Antibodies were measured by flow cytometry, and cellular responses were measured by IFN-gamma enzyme-linked immunospot and chromium release assays. Cellular responses in BALB/c and C57BL/6 mice were mapped using overlapping 15-mer PSMA peptides. A Good Laboratory Practice-compliant toxicology study was conducted in rabbits.


RESULTS
PSMA-VRP directed high-level expression of active PSMA. Robust T-cell and B-cell responses were elicited by a single injection of 2 x 10(5) infectious units, and responses were boosted following repeat immunizations. Anti-PSMA responses were detected following three immunizations with 10(2) infectious units and increased with increasing dose. PSMA-VRP was more immunogenic than adjuvanted PSMA protein. Responses to PSMA-VRP were characterized by Th-1 cytokines, potent CTL activity, and IgG2a/IgG2b antibodies. T-cell responses in BALB/c and C57BL/6 mice were directed toward different PSMA peptides. Immunogenic doses of PSMA-VRP were well tolerated in mice and rabbits.


CONCLUSIONS
PSMA-VRP elicited potent cellular and humoral immunity in mice, and specific anti-PSMA responses were boosted on repeat dosing. PSMA-VRP represents a promising approach for immunotherapy of prostate cancer.
Durso
Robert J
RJ
Progenics Pharmaceuticals, Inc., Tarrytown, New York 10591, USA.
Andjelic
Sofija
S
Gardner
Jason P
JP
Margitich
Dennis J
DJ
Donovan
Gerald P
GP
Arrigale
Robert R
RR
Wang
Xinning
X
Maughan
Maureen F
MF
Talarico
Todd L
TL
Olmsted
Robert A
RA
Heston
Warren D W
WD
Maddon
Paul J
PJ
Olson
William C
WC
D000524:Alphavirus / Q000235:genetics*; D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry / Q000235:genetics*; D019496:Cancer Vaccines / Q000737:chemistry*; D000939:Epitopes / Q000737:chemistry; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry / Q000235:genetics*; D007107:Immune System; D007167:Immunotherapy / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy; D011817:Rabbits; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism
D000954:Antigens, Surface; D019496:Cancer Vaccines; D000939:Epitopes; D010455:Peptides; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II