Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination
Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination
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DOI：
10.1073/pnas.1008051107
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发表时间：
2010-08-03
影响因子：
11.1
通讯作者：
Berneman, Zwi N.
中科院分区：
文献类型：
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作者：
Van Tendeloo, Viggo F.;de Velde, Ann Van;Berneman, Zwi N.
使用负载肿瘤抗原的树突状细胞进行主动免疫有望用于癌症的辅助治疗，以根除或控制残留疾病，但到目前为止，大多数树突状细胞试验都是在肿瘤负载较高的终末期癌症患者中进行的。在一项 I/II 期试验中，我们研究了自体树突状细胞疫苗接种对 10 名急性髓系白血病 (AML) 患者的效果。 Wilms 肿瘤 1 蛋白 (WT1) 是一种几乎通用的肿瘤抗原，因其在白血病发生中的既定作用和卓越的免疫原性特征而被选为免疫治疗靶点。两名化疗后部分缓解的患者在皮内注射全长 WT1 mRNA 电穿孔树突状细胞后进入完全缓解。在这两名患者和其他三名完全缓解的患者中，树突状细胞疫苗接种后，AML 相关肿瘤标志物恢复正常，与分子缓解的诱导相一致。临床反应与疫苗相关的 WT1 特异性 CD8(+) T 细胞频率增加（通过肽/HLA-A*0201 四聚体染色检测）以及疫苗接种后激活的自然杀伤细胞水平升高相关。此外，接种疫苗的患者表现出WT1特异性产生IFN-γ的CD8(+) T细胞水平增加以及一般免疫激活的特征。这些数据支持进一步开发携带 WT1 mRNA 的树突状细胞疫苗接种作为缓解后治疗，以防止 AML 患者完全复发。
Active immunization using tumor antigen-loaded dendritic cells holds promise for the adjuvant treatment of cancer to eradicate or control residual disease, but so far, most dendritic cell trials have been performed in end-stage cancer patients with high tumor loads. Here, in a phase I/II trial, we investigated the effect of autologous dendritic cell vaccination in 10 patients with acute myeloid leukemia (AML). The Wilms' tumor 1 protein (WT1), a nearly universal tumor antigen, was chosen as an immunotherapeutic target because of its established role in leukemogenesis and superior immunogenic characteristics. Two patients in partial remission after chemotherapy were brought into complete remission after intradermal administration of full-length WT1 mRNA-electroporated dendritic cells. In these two patients and three other patients who were in complete remission, the AML-associated tumor marker returned to normal after dendritic cell vaccination, compatible with the induction of molecular remission. Clinical responses were correlated with vaccine-associated increases in WT1-specific CD8(+) T cell frequencies, as detected by peptide/HLA-A*0201 tetramer staining, and elevated levels of activated natural killer cells postvaccination. Furthermore, vaccinated patients showed increased levels of WT1-specific IFN-gamma-producing CD8(+) T cells and features of general immune activation. These data support the further development of vaccination with WT1 mRNA-loaded dendritic cells as a postremission treatment to prevent full relapse in AML patients.