Induction of autoantibodies to syngeneic prostate-specific membrane antigen by xenogeneic vaccination

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
International Journal of Cancer (Impact Factor: 5.01). 09/2005; 116(3):415-21. DOI: 10.1002/ijc.21014
Source: PubMed

ABSTRACT Prostate-specific membrane antigen (PSMA) is a prototypical differentiation antigen expressed on normal and neoplastic prostate epithelial cells, and on the neovasculature of many solid tumors. Monoclonal antibodies specific for PSMA are in development as therapeutic agents. Methodologies to actively immunize against PSMA may be limited by immunologic ignorance and/or tolerance that restrict the response to self-antigens. Our studies have previously shown that xenogeneic immunization with DNA vaccines encoding melanosomal differentiation antigens induces immunity in a mouse melanoma model. Here we apply this approach to PSMA to establish proof of principle in a mouse model. Immunization with xenogeneic human PSMA protein or DNA induced antibodies to both human and mouse PSMA in mice. Monoclonal antibodies specific for mouse PSMA were generated to analyze antibody isotypes and specificity for native and denatured PSMA at the clonal level. Most antibodies recognized denatured PSMA, but C57BL/6 mice immunized with xenogeneic PSMA DNA followed by a final boost with xenogeneic PSMA protein yielded autoantibodies that reacted with native folded mouse PSMA. Monoclonal antibodies were used to confirm the expression of PSMA protein in normal mouse kidney. These results establish the basis for clinical trials to test PSMA DNA vaccines in patients with solid tumors that either express PSMA directly or that depend on normal endothelial cells expressing PSMA for their continued growth.

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Available from: Vandana Turaga, Aug 23, 2015
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    • "Therefore, it may be affected by a manner unrelated to the effect of the therapy on tumor, and is the cause of the patients' great anxiety or overstated diagnostic expectations [29] [30]. The prostate-specific membrane antigen (PSMA) is expressed in both the benign and the neoplastic prostatic epithelial cells and in other tissues, such as kidney, liver, and brain [31]. It is upregulated in hormone-resistant states and in metastatic disease. "
    Molecular Imaging, 03/2012; , ISBN: 978-953-51-0359-2
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    • "Application of xenogeneic tumor-associated antigens is another interesting strategy to overcome some of the obstacles mentioned above. The magnitude of an antitumor response is clearly improved by using a tumor-associated antigen obtained from a different species sharing critical epitopes flanked by xenogeneic protein sequences further stimulating the antitumor response [16] [17] [18] [19]. The delivery of such xenogeneic tumor-associated antigens by DNA vaccination may be a promising venue to the design of a successful strategy. "
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    ABSTRACT: AIM: To evaluate whether the combination of recom- binant chicken fibroblast growth factor receptor -1 (FGFR-1) protein vaccine (cFR-1) combined with low- dose gemcitabine would improve anti-tumor efficacy in a mouse CT26 colon adenocarcinoma (CT26) model. METHODS: The CT26 model was established in BABL/c mice. Seven days after tumor cell injection, mice were randomly divided into four groups: combination therapy, cFR-1 alone, gemcitabine alone, and normal saline groups. Tumor growth, survival rate of tumor-bearing mice, and systemic toxicity were observed. The presence of anti-tumor auto-antibodies was detected by Western blot analysis and enzyme-linked immunospot assay, microvessel density (MVD) of the tumors and tumor cell proliferation were detected by Immunohistochemistry staining, and tumor cell apoptosis was detected by TdT- mediated biotinylated-dUTP nick end label staining. RESULTS: The combination therapy results in apparent decreases in tumor volume, microvessel density and tumor cell proliferation, and an increase in apoptosis without obvious side-effects as compared with either therapy alone or normal control groups. Also, both auto- antibodies and the antibody-producing B cells against mouse FGFR-1 were detected in mice immunized with cFR-1 vaccine alone or with combination therapy, but not in non-immunized mice. In addition, the deposition of auto-antibodies on endothelial cells from mice immunized with cFR-1 was observed by immunofluorescent stain- ing, but not on endothelial cells from control groups. Synergistic indexes of tumor volume, MVD, cell apoptosis and proliferation in the combination therapy group were 1.71 vs 1.15 vs 1.11 and 1.04, respectively, 31 d after tumor cell injection. CONCLUSION: The combination of cFR-1-mediated anti- angiogenesis and low-dose gemcitabine synergistically enhances the anti-tumor activity without overt toxicity in mice.
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