title: Immunological targeting of tumor cells undergoing an epithelial-mesenchymal transition via a recombinant brachyury-yeast vaccine.
abstract: The embryonic T-box transcription factor brachyury is aberrantly expressed in a range of human tumors. Previous studies have demonstrated that brachyury is a driver of the epithelial-mesenchymal transition (EMT), a process associated with cancer progression. Brachyury expression in human tumor cells enhances tumor invasiveness in vitro and metastasis in vivo, and induces resistance to various conventional therapeutics including chemotherapy and radiation. These characteristics, and the selective expression of brachyury for a range of human tumor types vs. normal adult tissues, make brachyury an attractive tumor target. Due to its intracellular localization and the "undruggable" character of transcription factors, available options to target brachyury are currently limited. Here we report on the development and characterization of an immunological platform for the efficient targeting of brachyury-positive tumors consisting of a heat-killed, recombinant Saccharomyces cerevisiae (yeast)-brachyury vector-based vaccine (designated as GI-6301) that expresses the full-length human brachyury protein. We demonstrate that human dendritic cells treated with recombinant yeast-brachyury can activate and expand brachyury-specific CD4+ and CD8+ T cells in vitro that, in turn, can effectively lyse human tumor cells expressing the brachyury protein. Vaccination of mice with recombinant yeast-brachyury is also shown here to elicit brachyury-specific CD4+ and CD8+ T-cell responses, and to induce anti-tumor immunity in the absence of toxicity. Based on these results, a Phase I clinical trial of GI-6301 is currently ongoing in patients with advanced tumors; to our knowledge, this is the first vaccine platform aimed at targeting a driver of tumor EMT that has successfully reached the clinical stage.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Duane H
authors.initials: DH
authors.lastname: Hamilton
authors.forename: Mary T
authors.initials: MT
authors.lastname: Litzinger
authors.forename: Alessandra
authors.initials: A
authors.lastname: Jales
authors.forename: Bruce
authors.initials: B
authors.lastname: Huang
authors.forename: Romaine I
authors.initials: RI
authors.lastname: Fernando
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
authors.forename: Andressa
authors.initials: A
authors.lastname: Ardiani
authors.forename: David
authors.initials: D
authors.lastname: Apelian
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: Claudia
authors.initials: C
authors.lastname: Palena
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology*; D005260:Female; D005326:Fetal Proteins / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology*; D014945:Wound Healing / Q000276:immunology; D000098908:Brachyury Protein
chemical_list: D019496:Cancer Vaccines; D005326:Fetal Proteins; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein