Abstract CN04-01: Targeting the epithelial-mesenchymal transition via brachyury-based cancer vaccines
Authors: Palena Claudia , Hamilton Duane H. , David Justin M. , Dominguez Charli , Heery Christopher R. , Gulley James L. , Schlom Jeffrey 
Published: May 2016

Abstract
Carcinoma cells undergo profound phenotypic changes during progression towards metastasis. One such phenotypic modulation is the epithelial-mesenchymal transition (EMT), an embryonically relevant process that can be reactivated in tumor cells, resulting in the acquisition of metastatic propensity, stem-like cell properties and resistance to a variety of anti-cancer therapies, including chemotherapy, radiation and some small molecule targeted therapies. Targeting of EMT is now emerging as a novel intervention against tumor progression. Brachyury, a transcription factor of the T-box family, is a driver of the phenomenon of EMT in human carcinomas. High levels of brachyury have been demonstrated in several human tumors, including chordoma, hemangioblastoma, and a range of human carcinomas such as lung, breast, colon and prostate, while brachyury is absent in the majority of adult normal tissues. In preclinical studies, brachyury has been shown to induce expression of molecules associated with the mesenchymal phenotype in carcinoma cells, to promote cell motility and invasiveness in vitro, and to favor metastatic dissemination in xenograft models. In addition to its role in tumor EMT, several studies have now also shown that the expression of brachyury is a predictor of poor prognosis in lung, breast, hepatocellular and prostate cancer, and it has been recently suggested to play a predominant role in triple negative vs. non-triple negative breast tumors. We propose the use of cancer vaccines that target brachyury as a strategy to directly eradicate tumor cells undergoing the phenomenon of EMT. Brachyury fulfills two major requirements to be used as a target for vaccine approaches: (a) is a highly tumor restricted molecule, and (b) is highly immunogenic, as demonstrated by the ability to expand brachyury-specific cytotoxic T lymphocytes from the blood of cancer patients which, in turn, can lyse tumor cells that express the brachyury protein. Based on these observations, our laboratory has collaboratively developed two brachyury-based cancer vaccines that are currently undergoing clinical evaluation. A recombinant yeast-brachyury vaccine expressing the full-length brachyury protein has demonstrated anti-tumor activity in murine models in the absence of toxicity. A Phase I clinical trial of this vaccine has now been completed in patients with advanced carcinomas or chordoma, demonstrating ability to induce multifunctional, brachyury-specific CD8+ and CD4+ T-cell responses in patients post- vs. pre-vaccination, with some evidence of disease control in absence of toxicity. In addition, a recombinant poxviral vaccine encoding brachyury and three T-cell costimulatory molecules, designated MVA-brachyury-TRICOM, is currently undergoing Phase I clinical testing in patients with advanced tumors. To our knowledge, yeast-brachyury and MVA-brachyury-TRICOM are the first vaccines targeting a driver of the phenomenon of EMT that have successfully entered clinical development. Phase II studies with these vaccines are now ongoing and planned. Multiple preclinical studies are being conducted to optimize the combinatorial use of these vaccines with other anti-cancer agents, including checkpoint inhibitors and other agents. We hypothesize that eradication of brachyury-expressing cancer cells will result in clinical benefit by reducing the number of tumor cells with stem-like characteristics, including invasive/metastatic potential and resistance to conventional therapies.
References: J Clin Invest 120(2):533-44; Clin Cancer Res 18(14):3868-79; Oncotarget 4(10):1777-90; J Natl Cancer Inst 106(5); Cancer Immunol Res. PMID: 26130065; Cancer Res 74(9):2510-9
Citation Format: Claudia Palena, Duane H. Hamilton, Justin M. David, Charli Dominguez, Christopher R. Heery, James L. Gulley, Jeffrey Schlom. Targeting the epithelial-mesenchymal transition via brachyury-based cancer vaccines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN04-01.