title: Dual antigen target-based immunotherapy for prostate cancer eliminates the growth of established tumors in mice.
abstract: OBJECTIVE
  We have previously shown that immunization with an adenovirus vector carrying an individual antigen induces antigen-specific CD8 T cells actively engaged in the destruction of tumor cells expressing the cognate antigen. In order to expand the range of antitumor responses beyond an individual antigen, we designed a recombinant adenovirus type 5 (rAd5) carrying a fusion construct of two full-length antigens. We used this adenovirus vector to test the concept that multiantigenic effector T cells could be generated simultaneously following a single immunization.
  
  
  METHODS
  To perform the rAd5 constructs, we selected a combination of prostate-specific antigen (PSA) and prostate stem cell antigen (PSCA) genes based on their restricted distribution within the prostate tissue and their association with the development and progression of prostate cancer.
  
  
  RESULTS
  Immunization of mice with rAd5 vector carrying a fusion construct of PSA and PSCA (Ad5-PSA/PSCA) simultaneously induced the expansion of anti-PSA and anti-PSCA CD8 T cells, as measured by intracellular cytokine staining for IFN-γ. The antigen-specific T-cell responses that developed were efficient in eliminating the target cells expressing cognate antigens measured by an in vivo cytotoxic T-cell assay. The in vivo tumor growth study showed that immunization of mice with Ad5-PSA/PSCA vaccine induced strong antitumor immunity when challenged with mouse prostate tumor cell lines (RM11) expressing human PSA (RM11/PSA). To further analyze the impact on therapeutic efficacy of Ad5-PSA/PSCA vaccine against the tumor cells expressing PSA and PSCA (RM11-PSA/PSCA) antigens, we injected mice with Ad5-PSA/PSCA vaccine. The vaccine inhibited the growth of established tumors with 80% of the mice becoming tumor free. These data provide useful information that antigen-specific effector T cells can be generated simultaneously and that their additive antitumor effect has the potential to eliminate the growth of established tumors. Therefore, the immunotherapy approach of using the simultaneous targeting of dual antigens associated with prostate cancer may have important implications for human clinical trials.
authors.affiliation: Veterans Affairs Medical Center, Kansas City, MO, USA. dkaran@kumc.edu
authors.forename: Dev
authors.initials: D
authors.lastname: Karan
authors.forename: Seema
authors.initials: S
authors.lastname: Dubey
authors.forename: Peter
authors.initials: P
authors.lastname: Van Veldhuizen
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Holzbeierlein
authors.forename: Ossama
authors.initials: O
authors.lastname: Tawfik
authors.forename: J Brantley
authors.initials: JB
authors.lastname: Thrasher
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000276:immunology; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D019444:Vaccines, DNA; D007371:Interferon-gamma; D010047:Ovalbumin; D017430:Prostate-Specific Antigen