title: Combination therapy with a second-generation androgen receptor antagonist and a metastasis vaccine improves survival in a spontaneous prostate cancer model.
abstract: OBJECTIVE
  Enzalutamide, a second-generation androgen antagonist, was approved by the U.S. Food and Drug Administration (FDA) for castration-resistant prostate cancer (CRPC) treatment. Immunotherapy has been shown to be a promising strategy for prostate cancer. This study was performed to provide data to support the combination of enzalutamide and immunotherapy for CRPC treatment.
  
  
  METHODS
  Male C57BL/6 or TRAMP (transgenic adenocarcinoma of the mouse prostate) prostate cancer model mice were exposed to enzalutamide and/or a therapeutic vaccine targeting Twist, an antigen involved in epithelial-to-mesenchymal transition and metastasis. The physiologic and immunologic effects of enzalutamide were characterized. The generation of Twist-specific immunity by Twist-vaccine was assessed. Finally, the combination of enzalutamide and Twist-vaccine to improve TRAMP mice overall survival was evaluated.
  
  
  RESULTS
  Enzalutamide mediated immunogenic modulation in TRAMP-C2 cells. In vivo, enzalutamide mediated reduced genitourinary tissue weight, enlargement of the thymus, and increased levels of T-cell excision circles. Because no changes were seen in T-cell function, as determined by CD4(+) T-cell proliferation and regulatory T cell (Treg) functional assays, enzalutamide was determined to be immune inert. Enzalutamide did not diminish the ability of Twist-vaccine to generate Twist-specific immunity. Twist was confirmed as a valid tumor antigen in TRAMP mice by immunohistochemistry. The combination of enzalutamide and Twist-vaccine resulted in significantly increased overall survival of TRAMP mice compared with other treatment groups (27.5 vs. 10.3 weeks). Notably, the effectiveness of the combination therapy increased with disease stage, i.e., the greatest survival benefit was seen in mice with advanced-stage prostate tumors.
  
  
  CONCLUSIONS
  These data support the combination of enzalutamide and immunotherapy as a promising treatment strategy for CRPC. Clin Cancer Res; 19(22); 6205-18. ©2013 AACR.
authors.affiliation: Authors' Affiliations: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; Medivation Inc., San Francisco, California; and GlobeImmune Inc., Louisville, Colorado.
authors.forename: Andressa
authors.initials: A
authors.lastname: Ardiani
authors.forename: Benedetto
authors.initials: B
authors.lastname: Farsaci
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Rogers
authors.forename: Andy
authors.initials: A
authors.lastname: Protter
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Guo
authors.forename: Thomas H
authors.initials: TH
authors.lastname: King
authors.forename: David
authors.initials: D
authors.lastname: Apelian
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000401:mortality; D059002:Androgen Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000401:mortality; D034622:RNA Interference; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000187:drug effects; D013534:Survival; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000276:immunology; D014566:Urogenital System / Q000187:drug effects; D014611:Vaccination
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D019496:Cancer Vaccines; D009570:Nitriles; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D051879:Twist-Related Protein 1; D010669:Phenylthiohydantoin; C540278:enzalutamide
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