title: Phase II trial of Modified Vaccinia Ankara (MVA) virus expressing 5T4 and high dose Interleukin-2 (IL-2) in patients with metastatic renal cell carcinoma.
abstract: BACKGROUND
  Interleukin-2 (IL-2) induces durable objective responses in a small cohort of patients with metastatic renal cell carcinoma (RCC) but the antigen(s) responsible for tumor rejection are not known. 5T4 is a non-secreted membrane glycoprotein expressed on clear cell and papillary RCCs. A modified vaccinia virus Ankara (MVA) encoding 5T4 was tested in combination with high-dose IL-2 to determine the safety, objective response rate and effect on humoral and cell-mediated immunity.
  
  
  METHODS
  25 patients with metastatic RCC who qualified for IL-2 were eligible and received three immunizations every three weeks followed by IL-2 (600,000 IU/kg) after the second and third vaccinations. Blood was collected for analysis of humoral, effector and regulatory T cell responses.
  
  
  RESULTS
  There were no serious vaccine-related adverse events. While no objective responses were observed, three patients (12%) were rendered disease-free after nephrectomy or resection of residual metastatic disease. Twelve patients (48%) had stable disease which was associated with improved median overall survival compared to patients with progressive disease (not reached vs. 28 months, p = 0.0261). All patients developed 5T4-specific antibody responses and 13 patients had an increase in 5T4-specific T cell responses. Although the baseline frequency of Tregs was elevated in all patients, those with stable disease showed a trend toward increased effector CD8+ T cells and a decrease in Tregs.
  
  
  CONCLUSIONS
  Vaccination with MVA-5T4 did not improve objective response rates of IL-2 therapy but did result in stable disease associated with an increase in the ratio of 5T4-specific effector to regulatory T cells in selected patients.
  
  
  BACKGROUND
  ISRCTN83977250.
authors.affiliation: Tumor Immunology Laboratory, Division of Surgical Oncology, Columbia University, New York, NY, USA. hlk2003@columbia.edu
authors.forename: Howard L
authors.initials: HL
authors.lastname: Kaufman
authors.forename: Bret
authors.initials: B
authors.lastname: Taback
authors.forename: William
authors.initials: W
authors.lastname: Sherman
authors.forename: Dae Won
authors.initials: DW
authors.lastname: Kim
authors.forename: William H
authors.initials: WH
authors.lastname: Shingler
authors.forename: Dorota
authors.initials: D
authors.lastname: Moroziewicz
authors.forename: Gail
authors.initials: G
authors.lastname: DeRaffele
authors.forename: Josephine
authors.initials: J
authors.lastname: Mitcham
authors.forename: Miles W
authors.initials: MW
authors.lastname: Carroll
authors.forename: Richard
authors.initials: R
authors.lastname: Harrop
authors.forename: Stuart
authors.initials: S
authors.lastname: Naylor
authors.forename: Seunghee
authors.initials: S
authors.lastname: Kim-Schulze
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D014408:Biomarkers, Tumor / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019444:Vaccines, DNA; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D019496:Cancer Vaccines; D007376:Interleukin-2; D008562:Membrane Glycoproteins; C504058:TroVax; D019444:Vaccines, DNA; C063709:trophoblastic glycoprotein 5T4, human