Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury
Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury
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DOI：
10.1158/1078-0432.ccr-17-1087
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发表时间：
2017-11-15
影响因子：
11.5
通讯作者：
Gulley, James L.
中科院分区：
文献类型：
--
作者：
Heery, Christopher R.;Palena, Claudia;Gulley, James L.
目的：在临床前研究中已经显示转录因子brachyury是上皮向间充质转化（EMT）和对人肿瘤细胞治疗的抗性的驱动因素。本研究描述了一种修饰的牛痘安卡拉（MVA）载体为基础的疫苗表达的转基因brachyury和三个人的共刺激分子（B7.1，ICAM 1，和LFA-3，指定TRICOM）和一个阶段I研究与此vaccine.Experimental Design：人树突状细胞（DC）感染MVA-brachyury-TRICOM，以确定他们的能力，激活brachyury特异性T细胞。在晚期癌症患者（n = 38）中进行剂量递增I期研究（NCT 02179515）以确定安全性并鉴定短尾畸形特异性T细胞应答。在三个剂量水平中的任何一个剂量水平下，在癌症患者中均未观察到疫苗引起的剂量限制性毒性。1例可能与疫苗（腹泻）相关的一过性3级不良事件（AE）在未进行干预的情况下消退，并且在后续疫苗接种后未复发。与疫苗相关的所有其他AE均为一过性，
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, ICAM1, 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 brachyuryspecific 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