Phase I Trial of a Modified Vaccinia Ankara Priming Vaccine Followed by a Fowlpox Virus Boosting Vaccine Modified to Express Brachyury and Costimulatory Molecules in Advanced Solid Tumors
Phase I Trial of a Modified Vaccinia Ankara Priming Vaccine Followed by a Fowlpox Virus Boosting Vaccine Modified to Express Brachyury and Costimulatory Molecules in Advanced Solid Tumors
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DOI：
10.1634/theoncologist.2019-0932
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发表时间：
2019-12-26
期刊：
影响因子：
5.8
通讯作者：
Bilusic, Maruo
中科院分区：
文献类型：
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作者：
Collins, Julie M.;Donahue, Renee N.;Bilusic, Maruo
经验教训改良的安卡拉-巴伐利亚北欧（MVA-BN）-Brachyury牛痘后，鸡痘病毒-BN-Brachyury在晚期癌症患者中耐受良好。63%的患者在接种疫苗后对短尾畸形产生了CD 4+和/或CD 8 + T细胞应答。BN-Brachyury疫苗还诱导针对CEA和MUC 1的T细胞应答，CEA和MUC 1是级联抗原，即疫苗中未编码的抗原。背景Brachyury是一种转录因子，在上皮-间质转化、转移和肿瘤化疗耐药中起着不可或缺的作用。它在许多肿瘤类型中表达，很少在正常组织中表达，使其成为理想的免疫靶点。Bavarian Nordic（BN）-Brachyury由用改良的安卡拉牛痘（MVA）引发随后鸡痘病毒（FPV）加强的疫苗接种组成，每种疫苗编码Brachyury和共刺激分子的转基因。方法转移性实体瘤患者每月皮下注射2次MVA-Brachyury，8 × 10（8）感染单位（IU），随后是FPV-短尾型皮下注射，1 x 10（9）IU，每月6次，然后每3个月一次，持续2年。主要目的是确定安全性和耐受性。结果从2018年3月至2018年7月共入组11例患者（1例患者不可评价）。未观察到剂量限制性毒性。最常见的治疗相关不良事件是在所有患者中观察到的1/2级注射部位反应。最佳总体缓解为6例患者病情稳定，6个月无进展生存率为50%。在大多数患者中检测到针对短尾畸形和级联抗原CEA和MUC 1的T细胞。结论BN-Brachyury疫苗具有良好的耐受性，诱导了针对Brachyury和级联抗原的免疫应答，并显示出一定的临床效益。
Lessons LearnedModified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury followed by fowlpox virus-BN-Brachyury was well tolerated upon administration to patients with advanced cancer. Sixty-three percent of patients developed CD4+ and/or CD8+ T-cell responses to brachyury after vaccination. BN-Brachyury vaccine also induced T-cell responses against CEA and MUC1, which are cascade antigens, that is, antigens not encoded in the vaccines. Background Brachyury, a transcription factor, plays an integral role in the epithelial-mesenchymal transition, metastasis, and tumor resistance to chemotherapy. It is expressed in many tumor types, and rarely in normal tissues, making it an ideal immunologic target. Bavarian Nordic (BN)-Brachyury consists of vaccination with modified vaccinia Ankara (MVA) priming followed by fowlpox virus (FPV) boosting, each encoding transgenes for brachyury and costimulatory molecules. Methods Patients with metastatic solid tumors were treated with two monthly doses of MVA-brachyury s.c., 8 x 10(8) infectious units (IU), followed by FPV-brachyury s.c., 1 x 10(9) IU, for six monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability. Results Eleven patients were enrolled from March 2018 to July 2018 (one patient was nonevaluable). No dose-limiting toxicities were observed. The most common treatment-related adverse event was grade 1/2 injection-site reaction observed in all patients. Best overall response was stable disease in six patients, and the 6-month progression-free survival rate was 50%. T cells against brachyury and cascade antigens CEA and MUC1 were detected in the majority of patients. Conclusion BN-Brachyury vaccine is well tolerated and induces immune responses to brachyury and cascade antigens and demonstrates some evidence of clinical benefit.