title: Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury.
abstract: The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3+3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40- and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Heery
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: B Harpreet
authors.initials: BH
authors.lastname: Singh
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Myrna
authors.initials: M
authors.lastname: Rauckhorst
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Marté
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Renee N
authors.initials: RN
authors.lastname: Donahue
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Italia
authors.initials: I
authors.lastname: Grenga
authors.affiliation: GlobeImmune, Inc., Louisville, Colorado.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Rodell
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: William
authors.initials: W
authors.lastname: Dahut
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Arlen
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ravi A
authors.initials: RA
authors.lastname: Madan
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.affiliation: Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. gj50i@nih.gov.
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D002817:Chordoma / Q000276:immunology / Q000628:therapy*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000628:therapy*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005326:Fetal Proteins / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology; D012441:Saccharomyces cerevisiae / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology*; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000098908:Brachyury Protein
chemical_list: D019496:Cancer Vaccines; D005326:Fetal Proteins; D009363:Neoplasm Proteins; D020825:T-Box Domain Proteins; D015164:Vaccines, Inactivated; D000098908:Brachyury Protein