Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury.

Abstract

Purpose: The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine.Experimental Design: Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose-escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define safety and to identify brachyury-specific T-cell responses.Results: MVA-brachyury-TRICOM-infected human DCs activated CD8+ and CD4+ T cells specific against the self-antigen brachyury in vitro No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and ≤grade 2. Brachyury-specific T-cell responses were observed at all dose levels and in most patients.Conclusions: The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned. Clin Cancer Res; 23(22); 6833-45. ©2017 AACR.

• Authors: Christopher R Heery, Claudia Palena, Sheri McMahon, Renee N Donahue, Lauren M Lepone, Italia Grenga, Ulrike Dirmeier, Lisa Cordes, Jenn Marté, William Dahut, Harpreet Singh, Ravi A Madan, Romaine I Fernando, Duane H Hamilton, Jeffrey Schlom, James L Gulley
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 22 Pg. 6833-6845 (Nov 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28855356 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• B7-1 Antigen
• Biomarkers, Tumor
• CD58 Antigens
• Cancer Vaccines
• Fetal Proteins
• T-Box Domain Proteins
• Intercellular Adhesion Molecule-1
• Brachyury protein

Topics

• Adult
• Aged
• Aged, 80 and over
• B7-1 Antigen (genetics)
• Biomarkers, Tumor
• CD58 Antigens (genetics)
• Cancer Vaccines (genetics, immunology)
• Dendritic Cells (immunology, metabolism)
• Fetal Proteins (genetics, immunology)
• Genetic Vectors (genetics)
• Humans
• Intercellular Adhesion Molecule-1 (genetics)
• Lymphocyte Activation (genetics, immunology)
• Middle Aged
• Neoplasms (genetics, immunology, mortality, therapy)
• T-Box Domain Proteins (genetics, immunology)
• T-Cell Antigen Receptor Specificity (immunology)
• T-Lymphocytes (immunology, metabolism)
• Transgenes
• Treatment Outcome
• Vaccinia virus (genetics)