A phase I study of a yeast-based therapeutic cancer vaccine, GI-6301, targeting brachyury in patients with metastatic carcinoma.

Singh, Harpreet; Heery, Christopher R.; Marté, Jennifer L.; Farsaci, Benedetto; Madan, Ravi A.; Coyne, Geraldine Helen O'Sullivan; Palena, Claudia; Rodell, Timothy C.; Schlom, Jeffrey; Gulley, James L.

doi:10.1200/jco.2014.32.15_suppl.e14026

Cited by 4 publications

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“…Recently a Phase II clinical trial was initiated with the yeast-Brachyury vaccine GI-6301 ( www.clinicaltrials.gov , NCT02383498, 2015) to treat patients with advanced carcinomas. Preliminary results showed that Brachyury vaccine was well tolerated and Brachyury-specific CD8+ and/or CD4+ T-cell responses were present in the blood of some patients post- versus pre-vaccination [ 40 , 41 ]. This evidence together with results obtained in the present study indicates that Brachyury could be used as an immunotherapeutic target in patients with advanced PCa.…”

Section: Discussionmentioning

confidence: 99%

Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer

et al. 2016

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Prostate cancer (PCa) is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient management. Several mechanisms have been described to promote therapy resistance in PCa, such as androgen receptor (AR) activation, epithelial-to-mesenchymal transition (EMT), acquisition of stem cell properties and neuroendocrine transdifferentiation (NEtD). Recently, we identified Brachyury as a new biomarker of PCa aggressiveness and poor prognosis. In the present study we aimed to assess the role of Brachyury in PCa therapy resistance. We showed that Brachyury overexpression in prostate cancer cells lines increased resistance to docetaxel and cabazitaxel drugs, whereas Brachyury abrogation induced decrease in therapy resistance. Through ChiP-qPCR assays we further demonstrated that Brachyury is a direct regulator of AR expression as well as of the biomarker AMACR and the mesenchymal markers Snail and Fibronectin. Furthermore, in vitro Brachyury was also able to increase EMT and stem properties. By in silico analysis, clinically human Brachyury-positive PCa samples were associated with biomarkers of PCa aggressiveness and therapy resistance, including PTEN loss, and expression of NEtD markers, ERG and Bcl-2. Taken together, our results indicate that Brachyury contributes to tumor chemotherapy resistance, constituting an attractive target for advanced PCa patients.

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Section: Discussionmentioning

confidence: 99%

Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer

et al. 2016

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“…It has been previously shown that brachyury is immunogenic in humans [12, 35, 36] and based on those studies, a heat-killed recombinant Saccharomyces cerevisiae (yeast) brachyury vaccine and a MVA-poxviral vaccine encoding brachyury and a triad of costimulatory molecules (TRICOM) have been developed and characterized [26] and entered Phase I clinical testing in patients with advanced carcinomas or chordomas [28, 29, 37, 38]. In the context of clinical studies of brachyury-based vaccines, we believe MAb 54-1 could be of potential use to determine what type of tumors express brachyury and could therefore be targets, and to evaluate the presence of brachyury-positive tumor cells pre vs. post-treatment, therefore assisting in the interpretation of the efficacy of brachyury-based therapies.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of the embryonic transcription factor brachyury in human tumors detected with a novel rabbit monoclonal antibody

et al. 2014

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The embryonic transcription factor brachyury is overexpressed in a variety of human tumors, including lung, breast, colon and prostate carcinomas, chordomas and hemangioblastomas. In human carcinoma cells, overexpression of brachyury associates with the occurrence of the phenomenon of epithelial-mesenchymal transition (EMT), acquisition of metastatic propensity and resistance to a variety of anti-cancer therapeutics. Brachyury is preferentially expressed in human tumors vs. normal adult tissues, and high levels of this molecule associate with poor prognosis in patients with lung, colon and prostate carcinomas, and in breast cancer patients treated with adjuvant tamoxifen. Brachyury is immunogenic in humans and vaccines against this novel oncotarget are currently undergoing clinical investigation. While our group and others have employed various anti-brachyury antibodies to interrogate the above findings, we report here on the development and thorough characterization of a novel rabbit monoclonal antibody (MAb 54-1) that reacts with distinct high affinity and specificity with human brachyury. MAb 54-1 was successfully used in ELISA, western blot, immunofluorescence and immunohistochemistry assays to evaluate expression of brachyury in various human tumor cell lines and tissues. We propose the use of this antibody to assist in research studies of EMT and in prognostic studies for a range of human tumors.

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“…Based on these studies, a Phase I clinical trial has been initiated with the yeast-brachyury vaccine GI-6301 to treat patients with advanced carcinomas as well as chordomas (www.clinicaltrials.gov, 2013). The initial results of this Phase I trial have been reported (Heery et al, 2014; Singh et al, 2014); the yeast-brachyury vaccine was well tolerated and brachyury-specific CD8+ and/or CD4+ T-cell responses were present in the blood of some patients post- vs. pre-vaccination. These results demonstrated, for the first time in humans, that an EMT-TF could be targeted immunologically via vaccination.…”

Section: Targeting Of Emtmentioning

confidence: 99%

Immune Targeting of Tumor Epithelial–Mesenchymal Transition via Brachyury-Based Vaccines

Palena

Hamilton

2015

Advances in Cancer Research

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As a manifestation of their inherent plasticity, 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 reinstated by 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 the EMT is emerging as a novel intervention against tumor progression. This review focuses on the potential use of cancer vaccine strategies targeting tumor cells that exhibit mesenchymal-like features, with an emphasis on the current status of development of vaccine platforms directed against the T-box transcription factor brachyury, a novel cancer target involved in tumor EMT, stemness and resistance to therapies. Also presented is a summary of potential mechanisms of resistance to immune-mediated attack driven by EMT and the development of novel combinatorial strategies based on the use of agents that alleviate tumor EMT for an optimized targeting of plastic tumor cells that are responsible for tumor recurrence and the establishment of therapeutic refractoriness.

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A phase I study of a yeast-based therapeutic cancer vaccine, GI-6301, targeting brachyury in patients with metastatic carcinoma.

Cited by 4 publications

References 0 publications

Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer

Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer

Aberrant expression of the embryonic transcription factor brachyury in human tumors detected with a novel rabbit monoclonal antibody

Immune Targeting of Tumor Epithelial–Mesenchymal Transition via Brachyury-Based Vaccines

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