CTLA-4 blockade following relapse of malignancy after allogeneic stem cell transplantation is associated with T cell activation but not with increased levels of T regulatory cells.
CTLA-4 blockade following relapse of malignancy after allogeneic stem cell transplantation is associated with T cell activation but not with increased levels of T regulatory cells.
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DOI：
10.1016/j.bbmt.2010.08.005
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发表时间：
2011-05
影响因子：
4.3
通讯作者：
Ball, Edward D.
中科院分区：
文献类型：
--
作者：
Zhou, Jiehua;Bashey, Asad;Zhong, Ruikun;Corringham, Sue;Messer, Karen;Pu, Minya;Ma, Wenxue;Chut, Theresa;Soiffer, Robert;Mitrovich, Rachel C.;Lowy, Israel;Ball, Edward D.
细胞毒性T淋巴细胞相关抗原4（CTLA-4）是T细胞活化和增殖的关键负调节因子。伊匹单抗是一种人单克隆抗体，其特异性阻断CTLA-4与其配体的结合。为了检验伊匹单抗阻断CTLA-4可以增强移植物抗恶性肿瘤效应（GVM）而不显著影响移植物抗宿主病（GVHD）的假设，我们在异基因造血干细胞移植（allo-HSCT）后复发性恶性肿瘤患者中进行了伊匹单抗输注的I期临床试验。在这里，我们报告了29例患者单次给药伊匹单抗后外周血T淋巴细胞重建，T调节细胞（Treg）表达和T细胞活化标志物的分析。在伊匹单抗输注之前和之后从所有患者收集外周血样品。我们分析了所有病例的淋巴细胞免疫表型，包括CD 4 + CD 25 high细胞和T细胞活化标志物的水平。最后11例患者还评估了CD 4 + CD 25 highFoxp 3+细胞和CD 4 + T细胞中细胞内CTLA-4的水平。我们发现，与正常对照组相比，患者的CD 4和CD 45 RO阳性T细胞的基线水平较低。50%以上患者外周血淋巴细胞计数异常低下，CD 4或/和CD 8 T细胞计数异常低下，部分患者外周血B淋巴细胞计数阴性。在伊匹单抗输注之前，患者中的CD 4 + CD 25 high和CD 4 + CD 25 highFoxp 3 + T细胞的百分比均显著高于健康供体。29例患者中有20例显示基线时CD 4 + CD 25 low活化T细胞水平升高，而26例健康供体中仅3例具有这样的活化T细胞群体。伊匹单抗输注后，CD 4+和CD 8 + T淋巴细胞计数均显著增加。绝对淋巴细胞计数或表达活化标志物CD 69的T细胞无一致变化。然而，在伊匹单抗输注后的前60天内，29名患者中的20名患者的CD 4 + CD 25低T细胞和最后10名患者的CD 4 +HLA-DR+ T细胞增加。虽然CD 4 + CD 25 high和CD 4 + CD 25 highFoxp 3 + T细胞的百分比在观察期间显著降低，但绝对细胞计数没有变化。伊匹单抗输注后，CD 4 + CD 25 lo/− T细胞中的细胞内CTLA-4表达显著增加。我们得出结论，单次输注伊匹单抗阻断CTLA-4可在最高剂量水平下增加CD 4+和CD 4 +HLA-DR+ T淋巴细胞计数和细胞内CTLA-4表达。伊匹单抗输注后Treg细胞数量无显著变化。这些数据显示，在暴露于单剂量的易普利姆玛后，T细胞群发生显著变化。需要对多次给药进行进一步研究，以进一步探索这一现象，并将淋巴细胞亚群的变化与临床事件相关联。
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a key negative regulator of T cell activation and proliferation. Ipilimumab is a human monoclonal antibody that specifically blocks the binding of CTLA-4 to its ligand. To test the hypothesis that blockade of CTLA-4 by ipilimumab could augment graft-versus-malignancy effects (GVM) without a significant impact on graft-versus-host disease (GVHD), we conducted a phase I clinical trial of ipilimumab infusion in patients with relapsed malignancy following allogeneic hematopoietic stem cell transplant (allo-HSCT). Here we report the analysis of peripheral blood T lymphocyte reconstitution, T regulatory cell (Treg) expression and T cell activation markers after a single dose of ipilimumab in 29 patients. Peripheral blood samples were collected from all patients before and after ipilimumab infusion. We analyzed lymphocyte immunophenotyes, including levels of CD4+CD25high cells and T cell activation markers in all cases. Levels of CD4+CD25highFoxp3+ cells and intracellular CTLA-4 in CD4+ T cells were also assessed in the last 11 cases. We found that baseline levels of CD4 and CD45RO positive T cells were lower in patients compared to normal controls. More than 50% patients had abnormally low lymphocyte counts, either CD4 or/and CD8 T cells, and some had no circulating B lymphocyte. The percentages of both CD4+CD25high and CD4+CD25highFoxp3+ T cells were significantly higher in patients prior to ipilimumab infusion than in healthy donors. 20 of 29 patients showed an elevated level of CD4+CD25low activated T cells at baseline while only 3 of 26 healthy donors had such a population of activated T cells. After ipilimumab infusion, both CD4+ and CD8+ T lymphocyte counts significantly increased. There was no consistent change in absolute lymphocyte count, or in T cells expressing the activation marker CD69. However, CD4+CD25low T cells in 20 of 29 patients, and CD4+HLA-DR+ T cell in the last 10 patients increased in the first 60 days following ipilimumab infusion. Although the percentages of both CD4+CD25high and CD4+CD25highFoxp3+ T cells significantly decreased during the observation period, the absolute cell counts did not change. Intracellular CTLA-4 expression in CD4+ CD25lo/− T cells significantly increased after ipilimumab infusion. We conclude that CTLA-4 blockade by a single infusion of ipilimumab increased CD4+ and CD4+HLA-DR+ T lymphocyte counts and intracellular CTLA-4 expression at the highest dose level. There was no significant change in Treg cell numbers after ipilimumab infusion. These data show that significant changes in T cell populations occur upon exposure to a single dose of ipilimumab. Further studies with multiple doses are needed to explore this phenomenon further and to correlate changes in lymphocyte subpopulations with clinical events.
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影响因子：
10.1
作者：
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