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Identification of tumor associated immune responses against brachyury, a transcription factor and driver of EMT, in chordoma patients receiving a yeast-brachyury vaccine (gi-6301)
© Donahue et al.; licensee BioMed Central Ltd. 2014
Published: 6 November 2014
Brachyury is a tumor-associated antigen and transcription factor that drives the epithelial-to-mesenchymal transition (EMT) in human carcinomas. The aim of this study was to assess whether patients with chordoma, a rare tumor of the notochord that over-expresses brachyury, can elicit a brachyury-specific T cell response following yeast-Brachyury vaccination.
An expansion cohort of 7 patients with chordoma, enrolled in the Phase I clinical trial "Open Label Study to Evaluate the Safety and Tolerability of GI-6301 (Whole Heat-Killed Recombinant yeast Modified to Express Brachyury Protein) in Adults with Solid Tumors", NCT01519817, were assessed for brachyury-specific T cell responses. Patients received 40 yeast units of vaccine every 2 weeks, and monthly dosing following restaging at day 85. PBMCs from pre- and post-vaccination were cultured in a 7-day in vitro stimulation (IVS) with overlapping 15-mer peptides of the brachyury protein that was encoded in the vaccine, and IL7/IL15. Following the IVS, cells were rested for 4 days, and then re-stimulated with 15-mer peptides. HLA 15-mers and a mixture of 9-mer to 15-mers of CMV, EBV, Flu, and Tetanus Toxin (CEFT) served as negative and positive controls, respectively. Brachyury-specific T cell responses were analyzed by flow-cytometry intracellular staining (ICS) of CD4 and CD8 T lymphocytes for the cytokines IFN-γ, TNF, and IL-2, and the perforin/granzyme marker CD107a. Cells positive for ≥2 cytokines were considered multipotent T lymphocytes, while cells co-expressing at least one cytokine and positive for CD107a were classified as having a cytokine/lysis association. A patient was considered an immune responder if, after brachyury 15-mer IVS, the frequency of T lymphocytes positive for a cytokine or CD107a post-vaccine was >50% compared to both (1) pre-vaccine values and (2) HLA control post-vaccine.
43% of patients (3/7) had a response to brachyury, with 2 having only a CD4 response, and 1 having both a CD4 and CD8 response. Of the 3 immune responders, 1 had only a single cytokine response, 1 had multipotent T lymphocytes, and 1 had a cytokine/lysis association.
These findings show for the first time that chordoma patients immunized with brachyury, a tumor associated antigen and transcription factors that drives EMT, can develop a brachyury-specific T cell immune response. These results warrant further studies using this vaccine in additional chordoma patients.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.