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.