title: Phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without granulocyte-macrophage colony-stimulating factor, in patients with carcinoembryonic antigen-expressing carcinomas.
abstract: OBJECTIVE
  Our previous clinical experience with vaccinia and replication-defective avipox recombinant carcinoembryonic antigen (CEA) vaccines has demonstrated safety and clinical activity with a correlation between CEA-specific immune response and survival. Preclinical evidence demonstrated that the addition of the transgenes for three T-cell costimulatory molecules (B7-1, ICAM-1, LFA-3, designated TRICOM) results in a significant improvement in antigen-specific T-cell responses and antitumor activity. We describe here the first trial in humans of the CEA-TRICOM vaccines (also including an enhancer agonist epitope within the CEA gene).
  
  
  METHODS
  Fifty-eight patients with advanced CEA-expressing cancers were accrued to eight cohorts that involved vaccinations with the following: replication-defective fowlpox recombinant (rF)-CEA(6D)-TRICOM; primary vaccination with recombinant vaccinia (rV)-CEA(6D)-TRICOM plus rF-CEA(6D)-TRICOM booster vaccinations; and rV-CEA(6D)-TRICOM and then rF-CEA(6D)-TRICOM, plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with vaccines, or with divided doses of vaccine with GM-CSF. Vaccines were administered every 28 days for six doses and then once every 3 months. Reverting to treatments every 28 days was allowed if patients progressed on the 3-month schedule.
  
  
  RESULTS
  In this phase I study, no significant toxicity was observed. Twenty-three patients (40%) had stable disease for at least 4 months, with 14 of these patients having prolonged stable disease (> 6 months). Eleven patients had decreasing or stable serum CEA, and one patient had a pathologic complete response. Enhanced CEA-specific T-cell responses were observed in the majority of patients tested.
  
  
  CONCLUSIONS
  We demonstrated that the CEA-TRICOM vaccines are safe and can generate significant CEA-specific immune responses, and they seem to have clinical benefit in some patients with advanced cancer.
authors.affiliation: Lombardi Cancer Center, Georgetown University Medical Center, 3800 Reservoir Rd, NW, Washington, DC 20007, USA. marshalj@georgetown.edu
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
authors.forename: Philip M
authors.initials: PM
authors.lastname: Arlen
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Beetham
authors.forename: Kwong-Yok
authors.initials: KY
authors.lastname: Tsang
authors.forename: Rebecca
authors.initials: R
authors.lastname: Slack
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
authors.forename: Sandra
authors.initials: S
authors.lastname: Doren
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Grosenbach
authors.forename: Jimmy
authors.initials: J
authors.lastname: Hwang
authors.forename: Evelyn
authors.initials: E
authors.lastname: Fox
authors.forename: Lauretta
authors.initials: L
authors.lastname: Odogwu
authors.forename: Susie
authors.initials: S
authors.lastname: Park
authors.forename: Dennis
authors.initials: D
authors.lastname: Panicali
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018122:B7-1 Antigen / Q000235:genetics*; D018968:CD58 Antigens / Q000235:genetics*; D019496:Cancer Vaccines / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D005260:Female; D005587:Fowlpox virus / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D018122:B7-1 Antigen; D018968:CD58 Antigens; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D007074:Immunoglobulin G; D014614:Vaccines, Synthetic; D018799:Intercellular Adhesion Molecule-1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor