Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia
Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia
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DOI：
10.1038/leu.2010.29
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发表时间：
2010-04-01
期刊：
影响因子：
11.4
通讯作者：
Schmitt, M.
中科院分区：
文献类型：
--
作者：
Giannopoulos, K.;Dmoszynska, A.;Schmitt, M.
透明质酸介导的运动受体(RHAMM)是慢性淋巴细胞白血病(CLL)的肿瘤相关抗原。CD8(+)T细胞用受人类白细胞抗原(HL A)-A2限制的rhamm表位R3启动，能有效地杀伤rhamm(+)CLL细胞。因此，我们启动了R3多肽疫苗的I期临床试验。用不完全弗氏佐剂乳化的R3多肽(ILSLELMKL，300mUg/剂)免疫6例HLAA2(+)CLL患者，每2周免疫4次，同时给予粒细胞-巨噬细胞集落刺激因子(100mUg/剂)。在接种多肽疫苗的整个过程中进行了详细的免疫学分析。未观察到大于CTC I度皮肤毒性的严重不良反应。四名患者在接种疫苗期间表现出白细胞计数下降。在6名患者中，有5名患者的R3特异性CD8(+)T细胞与相应的多肽/人类白细胞抗原A2四聚体复合体一起被检测到；在5名患者中，有4名患者通过酶联免疫吸附斑点(ELISpot)试验对这些群体进行了功能验证。在有临床反应的患者中，我们发现R3特异性CD8(+)T细胞的频率增加，这些细胞表达高水平的CD107a，并产生干扰素-c和颗粒酶B来响应抗原攻击。有趣的是，在四名患者中，疫苗接种也与调节性T细胞的诱导有关。因此，在6例CLL患者中接种多肽疫苗是安全的，并能在一定程度上诱导针对肿瘤抗原RHAMM的CD8(+)T细胞反应。白血病(2010年)24798-805；doi：10.1038/leu 2010.29；2010年3月11日在线发布
The receptor for hyaluronic acid-mediated motility (RHAMM) is a tumor-associated antigen in chronic lymphocytic leukemia (CLL). CD8(+) T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)-A2, effectively lyse RHAMM(+) CLL cells. Therefore, we initiated a phase I clinical trial of R3 peptide vaccination. Six HLA-A2(+) CLL patients were vaccinated four times at biweekly intervals with the R3 peptide (ILSLELMKL; 300 mu g per dose) emulsified in incomplete Freund's adjuvant; granulocyte-macrophage colony stimulating factor (100 mu g per dose) was administered concomitantly. Detailed immunological analyses were conducted throughout the course of peptide vaccination. No severe adverse events greater than CTC I degrees skin toxicity were observed. Four patients exhibited reduced white blood cell counts during vaccination. In five of six patients, R3-specific CD8(+) T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in four of five patients using enzyme-linked immunosorbent spot (ELISpot) assays. In patients with clinical responses, we found increased frequencies of R3-specific CD8(+) T cells that expressed high levels of CD107a and produced both interferon-c and granzyme B in response to antigen challenge. Interestingly, vaccination was also associated with the induction of regulatory T cells in four patients. Thus peptide vaccination in six CLL patients was safe and could elicit to some extent specific CD8(+) T-cell responses against the tumor antigen RHAMM. Leukemia (2010) 24, 798-805; doi: 10.1038/leu.2010.29; published online 11 March 2010