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Preventive and therapeutic vaccination with PAP-3, a novel human prostate cancer peptide, inhibits carcinoma development in HLA transgenic mice

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Abstract

Conventional treatment of recurrent and metastasized prostate cancer (CaP) remains inadequate; this fact mandates development of alternative therapeutic modalities, such as specific active or passive immunotherapy. Previously, we reported the identification of a novel highly immunogenic HLA-A*0201-restricted Prostatic Acid Phosphatase-derived peptide (PAP-3) by a two-step in vivo screening in an HLA-transgenic (HHD) mouse system. In the present study we aimed at elucidating the efficiency of PAP-3-based vaccine upon active antitumor immunization. To this end we established preventive and therapeutic carcinoma models in HHD mice. The 3LL murine Lewis lung carcinoma clone D122 transduced to express HLA-A*0201 and PAP served as a platform for these models. The HLA-A*0201–PAP-3 complex specific recombinant single chain scFV-PAP-3 antibodies were generated and used to confirm an endogenous PAP processing resulting in PAP-3 presentation by HLA-A*0201. PAP-3 based vaccines significantly decreased tumor incidence in a preventive immunization setting. Therapeutic vaccination of HHD mice with PAP-3 led to rejection of early established tumors and to increase of mouse survival. These results strongly support a therapeutic relevance of the identified CTL epitope upon active antitumor immunization. The newly established carcinoma model presented herein might be a useful tool for cancer vaccine design and optimization.

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Abbreviations

CaP:

Prostate cancer

CTL:

Cytotoxic T-lymphocyte

DCs:

Dendritic cells

GM-CSF:

Granulocyte macrophage colony-stimulating factor

HLA:

Human leukocyte antigen

PAP:

Prostatic acid phosphatase

PBMC:

Peripheral blood mononuclear cells

PCTA-1:

Prostate carcinoma tumor antigen

PSA:

Prostate-specific antigen

PSMA:

Prostate-specific membrane antigen

PTI-1:

Prostatic carcinoma oncogene

STEAP:

Six-transmembrane epithelial antigen

TAA:

Tumor associated antigen

s.c.:

Subcutaneously

i.p.:

Intraperitoneally

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Acknowledgments

The authors thank Ms. Sara Rubinraut and Prof. Mati Fridkin for peptide synthesis. This study was supported by grants from the Horowitz Foundation, Israel Science Foundation, the Davis Lewis charitable fund, and the Ornest family fund (to L. Eisenbach). The authors certify that they have not entered into any agreement that could interfere with their access to the data on the research, nor upon their ability to analyze the data independently, to prepare manuscripts, and to publish them.

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Authors and Affiliations

  1. Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Arthur Machlenkin, Ilan Volovitz, Ezra Vadai, Adrian Paz, Ofir Goldberger, Esther Tzehoval & Lea Eisenbach

  2. Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, Israel

    Ronit Azriel-Rosenfeld & Itai Benhar

  3. Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel

    Avital Lev & Yoram Reiter

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  1. Arthur Machlenkin
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  2. Ronit Azriel-Rosenfeld
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  3. Ilan Volovitz
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  4. Ezra Vadai
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  5. Avital Lev
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  9. Esther Tzehoval
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  10. Itai Benhar
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  11. Lea Eisenbach
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Correspondence to Lea Eisenbach.

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Machlenkin, A., Azriel-Rosenfeld, R., Volovitz, I. et al. Preventive and therapeutic vaccination with PAP-3, a novel human prostate cancer peptide, inhibits carcinoma development in HLA transgenic mice. Cancer Immunol Immunother 56, 217–226 (2007). https://doi.org/10.1007/s00262-006-0184-0

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