Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer.
Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer.
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DOI：
10.1136/jitc-2021-003238
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发表时间：
2021-09
影响因子：
10.9
通讯作者：
Bilusic M
中科院分区：
文献类型：
--
作者：
DeMaria PJ;Lee-Wisdom K;Donahue RN;Madan RA;Karzai F;Schwab A;Palena C;Jochems C;Floudas C;Strauss J;Marté JL;Redman JM;Dombi E;Widemann B;Korchin B;Adams T;Pico-Navarro C;Heery C;Schlom J;Gulley JL;Bilusic M
MVA-BN-brachyury-TRICOM是一种基于重组载体的治疗性癌症疫苗，旨在诱导针对brachyury的免疫应答。Brachyury是一种在晚期癌症中过表达的转录因子，与治疗抗性、上皮向间质转化和转移潜力相关。MVA-BN-brachyury-TRICOM已在先前的皮下接种疫苗临床试验中证明了免疫原性和安全性。临床前研究表明，治疗性疫苗的静脉内给药可诱导上级CD 8 + T细胞应答、更高水平的全身性细胞因子释放以及更强的自然杀伤细胞活化和增殖。这是MVA-BN-brachyury-TRICOM静脉给药的首次人体研究。2020年1月至2021年3月，13名患者在美国国立卫生研究院临床中心接受了1期、开放标签、3+3设计、剂量递增研究的治疗。研究人群为患有晚期实体瘤的成人，富含脊索瘤，脊索瘤是一种罕见的脊索肉瘤，过表达短尾。在第1、22和43天在三个DL静脉内施用疫苗。采集血液样本以评估药物药代动力学和免疫激活。在基线、治疗后1个月和3个月进行成像。主要终点是根据剂量限制性毒性的频率确定的安全性和耐受性;次要终点是确定推荐的II期剂量。没有观察到剂量限制性毒性，也没有严重不良事件归因于疫苗。疫苗相关毒性与类别特征一致（即流感样症状）。观察到高达2级的细胞因子释放综合征，无不良结局。观察到发热、寒战/寒战和低血压的剂量效应趋势。研究结束时根据RECIST 1.1进行的客观缓解率的疗效分析显示，1例患者部分缓解，4例疾病稳定，8例疾病进展。3例病情稳定的患者以疼痛改善的形式出现临床获益。免疫相关者显示针对短尾畸形和其他肿瘤相关级联抗原的T细胞活化。MVA-BN-Brachyury-TRICOM疫苗静脉注射是安全和可耐受的。未达到最大耐受剂量。最大给药剂量为109感染单位，每3周一次，共3剂。选择该剂量作为推荐的II期剂量。NCT 04134312。
MVA-BN-brachyury-TRICOM is a recombinant vector-based therapeutic cancer vaccine designed to induce an immune response against brachyury. Brachyury, a transcription factor overexpressed in advanced cancers, has been associated with treatment resistance, epithelial-to-mesenchymal transition, and metastatic potential. MVA-BN-brachyury-TRICOM has demonstrated immunogenicity and safety in previous clinical trials of subcutaneously administered vaccine. Preclinical studies have suggested that intravenous administration of therapeutic vaccines can induce superior CD8+ T cell responses, higher levels of systemic cytokine release, and stronger natural killer cell activation and proliferation. This is the first-in-human study of the intravenous administration of MVA-BN-brachyury-TRICOM. Between January 2020 and March 2021, 13 patients were treated on a phase 1, open-label, 3+3 design, dose-escalation study at the National Institutes of Health Clinical Center. The study population was adults with advanced solid tumors and was enriched for chordoma, a rare sarcoma of the notochord that overexpresses brachyury. Vaccine was administered intravenously at three DLs on days 1, 22, and 43. Blood samples were taken to assess drug pharmacokinetics and immune activation. Imaging was conducted at baseline, 1 month, and 3 months post-treatment. The primary endpoint was safety and tolerability as determined by the frequency of dose-limiting toxicities; a secondary endpoint was determination of the recommended phase 2 dose. No dose-limiting toxicities were observed and no serious adverse events were attributed to the vaccine. Vaccine-related toxicities were consistent with class profile (ie, influenza-like symptoms). Cytokine release syndrome up to grade 2 was observed with no adverse outcomes. Dose-effect trend was observed for fever, chills/rigor, and hypotension. Efficacy analysis of objective response rate per RECIST 1.1 at the end of study showed one patient with a partial response, four with stable disease, and eight with progressive disease. Three patients with stable disease experienced clinical benefit in the form of improvement in pain. Immune correlatives showed T cell activation against brachyury and other tumor-associated cascade antigens. Intravenous administration of MVA-BN-brachyury-TRICOM vaccine was safe and tolerable. Maximum tolerated dose was not reached. The maximum administered dose was 109 infectious units every 3 weeks for three doses. This dose was selected as the recommended phase 2 dose. NCT04134312.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
11.5
作者：
Heery, Christopher R.;Palena, Claudia;Gulley, James L.
通讯作者：
Gulley, James L.
DOI：
10.1158/1078-0432.ccr-11-3211
发表时间：
2012-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Roselli M;Fernando RI;Guadagni F;Spila A;Alessandroni J;Palmirotta R;Costarelli L;Litzinger M;Hamilton D;Huang B;Tucker J;Tsang KY;Schlom J;Palena C
通讯作者：
Palena C
影响因子：
11.2
作者：
Onder, Tamer T.;Gupta, Piyush B.;Weinberg, Robert A.
通讯作者：
Weinberg, Robert A.
影响因子：
10.5
作者：
KISPERT, A;HERRMANN, BG;REUTER, R
通讯作者：
REUTER, R