Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced, CD34+-derived dendritic cell vaccination:: A phase I trial in metastatic melanoma
Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced, CD34+-derived dendritic cell vaccination:: A phase I trial in metastatic melanoma
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DOI：
10.1158/1078-0432.ccr-04-0602
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发表时间：
2004-08-15
影响因子：
11.5
通讯作者：
Anichini, A
中科院分区：
文献类型：
--
作者：
Di Nicola, M;Carlo-Stella, C;Anichini, A
目的：六名美国癌症联合委员会 IV 期黑色素瘤患者被纳入一项 I 期研究，使用编码人酪氨酸酶基因 (MVA-hTyr) 的改良痘苗安卡拉病毒转导的自体 CD34(+) 衍生树突状细胞进行疫苗接种。 实验设计：患者接受第一次静脉注射 1 X 108 MVA-hTyr 转导的树突状细胞，随后进行 3 次皮下注射。每隔 14 天注射一次。结果：除低烧（六名患者中的三名）、注射部位轻度红斑（六名患者中的五名）和白癜风（六名患者中的两名）外，治疗耐受性良好。部分反应，涉及 s.c. 的收缩。在 I 患者中观察到结节，后来通过手术切除，随后保持无病状态（>850 天）。通过人淋巴细胞抗原四聚体分析，在接种疫苗几天后，在 5 名 HLA-A*0201(+) 患者中的 4 名患者的外周血中，记录到针对酪氨酸酶 (368-376) 而不是针对 gp100(209-217) 的 T 细胞频率显着且通常持久的增加。此外，酪氨酸酶特异性T细胞的成熟表型与T细胞频率峰值同步转向T效应记忆/T终末分化阶段(CCR7(-)CD45RA(-/+))。通过对5名HLA-A*0201(+)患者外周血的酶联免疫斑点检测，我们发现该疫苗可以诱导针对HLA-A*0201/酪氨酸酶(368-376)和痘苗病毒HLA-A*0201/H3L(184-192)表位的干扰素释放效应细胞。此外，在两分之一的 HLA-A* DRBI-01501(+) 患者中，疫苗接种后甚至针对 HLA-DRBl-1501/酪氨酸酶 (386-406) 表位也引发了干扰素 γ 反应。结论：这些结果表明，用 MVA-hTyr 转导的树突细胞进行疫苗接种具有良好的耐受性，可能产生临床反应，并激活酪氨酸酶和酪氨酸酶。体内痘苗病毒特异性 T 细胞。这些数据表明 MVA 载体在将肿瘤相关抗原靶向树突状细胞以进行肿瘤免疫治疗方面具有广泛的用途。
Purpose: Six American Joint Committee on Cancer stage IV melanoma patients were enrolled into a Phase I study of vaccination with autologous CD34(+)-derived dendritic cells transduced with a modified vaccinia Ankara virus encoding human tyrosinase gene (MVA-hTyr).Experimental Design: Patients received a first intravenous injection of 1 X 108 MVA-hTyr-transduced dendritic cells, followed by three s.c. injections at a 14-day interval.Results: Treatment was well tolerated, except for lowgrade fever (three of six patients), mild erythema at injection site (five of six), and vitiligo (two of six). A partial response, involving shrinkage of an s.c. nodule, later surgically removed, was observed in I patient, who then remained disease-free (>850 days). By human lymphocyte antigen tetramer analysis, significant and often long-lasting increases in frequency of T cells directed to tyrosinase(368-376) but not to gp100(209-217) were documented in periphery of 4 of 5 HLA-A*0201(+) patients, a few days after vaccine administration. In addition, maturation phenotype of tyrosinase-specific T cell shifted toward the T effector memory/T terminally differentiate stages (CCR7(-)CD45RA(-/+)) in synchrony with the T-cell frequency peaks. By enzyme-linked immunospot in peripheral blood of five HLA-A*0201(+) patients, we found that the vaccine could induce interferon,gamma-releasing effector cells directed to HLA-A*0201/tyrosinase(368-376) and to vaccinia virus HLA-A*0201/H3L(184-192) epitopes. Moreover, an interferon gamma response after vaccination was elicited even against the HLA-DRBl-1501/tyrosinase(386-406) epitope in one out of two HLA-A* DRBI-01501(+) patients.Conclusions: These results indicate that vaccination with MVA-hTyr-transduced dendritic cells is well tolerated, can possibly produce clinical responses, and activates tyrosinase- and vaccinia virus-specific T cells in vivo. These data suggest a broad utility of the MVA vector for targeting tumor-associated antigens to dendritic cells for tumor immunotherapy.