Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines
Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines
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DOI：
10.1182/blood-2008-01-135319
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发表时间：
2008-08-01
期刊：
影响因子：
20.3
通讯作者：
Clay, Timothy M.
中科院分区：
文献类型：
--
作者：
Morse, Michael A.;Hobeika, Amy C.;Clay, Timothy M.
CD 4 + CD 25 + 9 + FoxP 3+调节性T（Treg）细胞限制抗原特异性免疫应答，并且是抑制抗癌免疫的原因。在临床前和临床研究中，我们评估了晚期恶性肿瘤患者FoxP 3 + Treg细胞耗竭的免疫后果。我们证明了靶向CD 25的免疫毒素（denileukin diftitox）在体外耗尽FoxP 3 + Treg细胞，降低Treg细胞功能，并增强抗原特异性T细胞应答。然后，我们试图通过Treg细胞耗竭来增强癌胚抗原（CEA）表达恶性肿瘤患者的抗肿瘤免疫应答。在初步研究（n = 15）中，地尼白介素diftitox作为单剂量或重复给药给予，随后用禽痘载体rF-CEA（6D）-TRICOM修饰的树突状细胞免疫。通过流式细胞术分析，我们报告了第一个直接证据，即在多次剂量的地尼白介素diftitox后，循环中的CD 4 + CD 25 + FoxP 3 + Treg细胞被耗尽。在多次给药组中观察到对CEA的T细胞应答的早期诱导和总体更大的暴露，但在单次给药组中未观察到。这些结果表明将Treg细胞耗竭与抗癌疫苗组合以增强肿瘤抗原特异性免疫应答的潜力，以及在优化疫苗努力中探索Treg耗竭策略的剂量和时间表的需要。本试验在www.clinicaltrials.gov上注册，编号为NCT 00128622。
CD4+CD25"'9"FoxP3+ regulatory T (Treg) cells limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. In preclinical and clinical studies, we assessed the immune consequences of FoxP3+ Treg-cell depletion in patients with advanced malignancies. We demonstrated that a CD25"'9" targeting immunotoxin (denileukin diftitox) depleted FoxP3+ Treg cells, decreased Treg-cell function, and enhanced antigen-specific T-cell responses in vitro. We then attempted to enhance antitumor immune responses in patients with carcinoembryonic antigen (CEA)-expressing malignancies by Treg-cell depletion. In a pilot study (n = 15), denileukin diftitox, given as a single dose or repeated dosing, was followed by immunizations with dendritic cells modified with the fowlpox vector rF-CEA(6D)-TRICOM. By flow cytometric analysis, we report the first direct evidence that circulating CD4+CD25"'9"FoxP3+ Treg cells are depleted after multiple doses of denileukin diftitox. Earlier induction of, and overall greater exposure to, the T-cell response to CEA was observed in the multiple-dose group, but not the single-dose group. These results indicate the potential for combining Treg-cell depletion with anticancer vaccines to enhance tumor antigen-specific immune responses and the need to explore dose and schedule of Treg depletion strategies in optimizing vaccine efforts. This trial was registered at www.clinicaltrials.gov as no. NCT00128622.