title: A vaccine strategy with multiple prostatic acid phosphatase-fused cytokines for prostate cancer treatment.
abstract: Immunotherapy is one of the attractive treatment strategies for advanced prostate cancer. The US Food and Drug Administration (FDA) previously approved the therapeutic vaccine, sipuleucel-T, which is composed of autologous antigen-presenting cells cultured with a fusion protein [prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GMCSF)]. Although sipuleucel-T has been shown to prolong the median survival of patients for 4.1 months, more robust therapeutic effects may be expected by modifying the vaccination protocol. In the present study, we aimed to develop and validate a novel vaccination strategy using multiple PAP-fused cytokines for prostate cancer treatment. Using a super gene expression (SGE) system that we previously established to amplify the production of a recombinant protein, significant amounts of PAP-fused cytokines [human GMCSF, interleukin-2 (IL2), IL4, IL7 and mouse GMCSF and IL4] were obtained. We examined the activity of the fusion proteins in vitro to validate their cytokine functions. A significant upregulation of dendritic cell differentiation from monocytes was achieved by PAP-GMCSF when used with the other PAP-fused cytokines. The PAP-fused human IL2 significantly increased the proliferation of lymphocytes, as determined by flow cytometry. We also investigated the in vivo therapeutic effects of multiple PAP-fused cytokines in a mouse prostate cancer model bearing prostate-specific antigen (PSA)- and PAP-expressing tumors. The simultaneous intraperitoneal administration of PAP-GMCSF, -IL2, -IL4 and -IL7 significantly prevented tumor induction and inhibited the tumor growth in the PAP-expressing tumors, yet not in the PSA-expressing tumors. The in vivo therapeutic effects with the multiple PAP-fused cytokines were superior to the effects of PAP-GMCSF alone. We thus demonstrated the advantages of the combined use of multiple PAP-fused cytokines including PAP-GMCSF, and propose a promising prostatic antigen-vaccination strategy to enhance the therapeutic effects.
authors: Department of Urology, Okayama University, Okayama, Japan.
authors: Kei
authors: K
authors: Fujio
authors: Department of Urology, Okayama University, Okayama, Japan.
authors: Masami
authors: M
authors: Watanabe
authors: Department of Urology, Okayama University, Okayama, Japan.
authors: Hideo
authors: H
authors: Ueki
authors: Department of Urology, Okayama University, Okayama, Japan.
authors: Shun-Ai
authors: SA
authors: Li
authors: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan.
authors: Rie
authors: R
authors: Kinoshita
authors: Department of Veterinary Nursing and Technology, School of Veterinary Science, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
authors: Kazuhiko
authors: K
authors: Ochiai
authors: Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan.
authors: Junichiro
authors: J
authors: Futami
authors: Department of Urology, Okayama University, Okayama, Japan.
authors: Toyohiko
authors: T
authors: Watanabe
authors: Department of Urology, Okayama University, Okayama, Japan.
authors: Yasutomo
authors: Y
authors: Nasu
authors: Department of Urology, Okayama University, Okayama, Japan.
authors: Hiromi
authors: H
authors: Kumon
mesh_terms: D000135:Acid Phosphatase / Q000494:pharmacology / Q000627:therapeutic use*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015870:Gene Expression; D005813:Genes, Synthetic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D016233:Immunotherapy, Active; D007378:Interleukins / Q000235:genetics / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D010957:Plasmids / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D007378:Interleukins; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase
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