Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909.
Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909.
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DOI：
10.1007/s00262-010-0929-7
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发表时间：
2011-02
期刊：
影响因子：
--
通讯作者：
Theobald M
中科院分区：
文献类型：
--
作者：
Kuball J;de Boer K;Wagner E;Wattad M;Antunes E;Weeratna RD;Vicari AP;Lotz C;van Dorp S;Hol S;Greenberg PD;Heit W;Davis HL;Theobald M
T细胞对来源于Wilms肿瘤基因（WT1）、蛋白酶3 （Pr3）和粘蛋白1 （MUC1）的抗原具有特异性，已被证明可以溶解急性髓性白血病（AML）母细胞和多发性骨髓瘤（MM）细胞，目前正在多个临床试验中探索通过疫苗接种增强或诱导这些肿瘤特异性T细胞的策略。为了测试由WT1-、Pr3-和muc1衍生的i类限制性肽和泛HLA-DR T辅助细胞表位（PADRE）或muc1辅助表位与CpG7909和MontanideISA51联合组成的疫苗的安全性和免疫原性，对4例AML患者和5例MM患者进行了重复接种。未观察到临床反应。既没有预先存在的也没有初始的WT1-/Pr3-/ muc1特异性CD8+ T细胞通过疫苗在体内扩增。相反，观察到疫苗特异性CD8+ T细胞显著下降。接种疫苗后，观察到padre特异性CD4+ T辅助细胞增加，但这些细胞似乎无法产生il - 2，具有调节性表型的CD4+ T细胞增加。考虑到使用相同抗原但不同佐剂的多个临床试验诱导疫苗特异性T细胞反应，我们的数据提醒我们，使用白血病相关抗原的疫苗接种与MontanideISA51和CpG7909联合使用时可能是有害的。考虑到临床试验的耗时和1/3正在进行的肽疫苗接种试验使用CpG和/或Montanide的事实，我们的数据需要考虑。本文的在线版本（doi:10.1007/s00262-010-0929-7）包含补充材料，可供授权用户使用。
T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration. The online version of this article (doi:10.1007/s00262-010-0929-7) contains supplementary material, which is available to authorized users.
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