title: Safety and immunologic response of a viral vaccine to prostate-specific antigen in combination with radiation therapy when metronomic-dose interleukin 2 is used as an adjuvant.
abstract: OBJECTIVE
  We have previously reported on the safety and immunologic response of a poxvirus-based vaccine encoding prostate-specific antigen (PSA) used in combination with radiation therapy in patients with localized prostate cancer. We hypothesized that a "metronomic" dose of interleukin 2 (IL-2) as a biological adjuvant would cause less toxicity while maintaining immunologic response.
  
  
  METHODS
  Eighteen patients with localized prostate cancer were treated in a single-arm trial using previously established doses of vaccine and radiation therapy. The vaccine used was a recombinant vaccinia virus engineered to encode PSA admixed with a recombinant vaccinia encoding the costimulatory molecule B7.1, followed by booster vaccinations with a recombinant fowlpox vector expressing PSA. Patients received a total of eight planned vaccination cycles, once every 4 weeks, with granulocyte-macrophage colony-stimulating factor given on days 1 to 4 and interleukin 2 (IL-2) at a dose of 0.6 MIU/M2 given from days 8 to 21 after each vaccination. Definitive external beam radiation therapy was initiated after the third vaccination cycle. Patients were evaluated for safety and immunologic response. Toxicity and immunologic activity were compared with the previously reported regimen containing a higher dose of IL-2.
  
  
  RESULTS
  Seventeen of 18 patients received all eight cycles of vaccine with IL-2. Five of eight HLA-A2+ patients evaluated had an increase in PSA-specific T cells of > or =3-fold. Toxicities were generally mild, with only seven vaccination cycles of 140 given resulting in grade 3 toxicities possibly attributable to IL-2.
  
  
  CONCLUSIONS
  Metronomic-dose IL-2 in combination with vaccine and radiation therapy is safe, can induce prostate-specific immune responses, and has immunologic activity similar to low-dose IL-2, with markedly reduced toxicities.
authors.affiliation: Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lechleider
authors.forename: Philip M
authors.initials: PM
authors.lastname: Arlen
authors.forename: Kwong-Yok
authors.initials: KY
authors.lastname: Tsang
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Junko
authors.initials: J
authors.lastname: Yokokawa
authors.forename: Vittore
authors.initials: V
authors.lastname: Cereda
authors.forename: Kevin
authors.initials: K
authors.lastname: Camphausen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: William L
authors.initials: WL
authors.lastname: Dahut
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects; D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D003131:Combined Modality Therapy; D005434:Flow Cytometry; D005587:Fowlpox virus / Q000235:genetics; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*; D011878:Radiotherapy; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D007376:Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017430:Prostate-Specific Antigen