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.

The embryonic Brachyury transcription factor is a novel biomarker of GIST aggressiveness and poor survival

“…*p \ 0.05. NS non significant to its role in the EMT process and involvement in metastatic development in solid tumors [17,19], Brachyury is positioned as a promising therapeutic target for advanced cancer patients [40,44]. To our knowledge, this is the first study that investigates Brachyury immunostaining and its relevance as a novel marker of aggressiveness in GIST.…”

T-box Transcription Factor Brachyury Is Associated with Prostate Cancer Progression and Aggressiveness

“…Several reports have demonstrated that EMT is critical for prostate cancer progression, as acquisition of mesenchymal features may favor dissemination and resistance to therapy (35). High levels of Brachyury have previously been reported in various types of cancer (5-9, 11) and a phase I clinical trial of a vaccine targeting Brachyury-positive tumors (GI-6301) is currently under way (36,37). Although prostate cancer is a leading cause of cancer-related deaths in men worldwide, a characterization of Brachyury biologic role in prostate tumorigenesis is missing.…”

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

“…Interestingly, TWIST may also be a viable immunotherapy target; recently TWIST was shown to be a TAA in the TRAMP-C2 subcutaneous model of murine PCa, and combined treatment of TRAMP-C2 xenografts in vivo with enzalutamide and a TWIST-specific vaccine significantly reduced tumor burden . Similarly, the T-box transcription factor Brachyury, which drives EMT in many cancers (Fernando et al 2010), has been identified as another PCa TAA, and yeast-based Brachyury vaccines are currently in development for the treatment of CRPC (Hamilton et al 2013). In addition, targeted therapies are in development to prevent identified drivers of NEPC and checkpoint molecule expression by tumors.…”