Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma.
Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma.
复制标题
DOI：
10.1084/jem.190.11.1669
复制
发表时间：
1999-12-06
期刊：
影响因子：
--
通讯作者：
Schuler G
中科院分区：
文献类型：
--
作者：
Thurner B;Haendle I;Röder C;Dieckmann D;Keikavoussi P;Jonuleit H;Bender A;Maczek C;Schreiner D;von den Driesch P;Bröcker EB;Steinman RM;Enk A;Kämpgen E;Schuler G
树突状细胞（DC）被认为是诱导癌症免疫的有前途的佐剂。我们使用成熟的单核细胞来源的 DC 来诱导对恶性黑色素瘤的抵抗。 DCs 用 Mage-3A1 肿瘤肽和记忆抗原、破伤风类毒素或结核菌素进行脉冲。 11 名晚期 IV 期黑色素瘤患者接受了 5 次 DC 疫苗接种，间隔 14 天，尽管进行了标准化疗，但病情仍在进展。前3次疫苗接种于皮肤内，皮下和皮内各注射3×106个DC，随后分别静脉注射6×106和12×106个DC两次。仅观察到轻微（小于或等于 II 级）副作用。对召回抗原的免疫力得到增强。 8/11 的患者中诱导了 Mage-3A1 特异性 CD8+ 细胞毒性 T 淋巴细胞 (CTL) 前体细胞的显着扩增。奇怪的是，这些免疫反应在静脉注射疫苗后往往会下降。 6/11 例患者的个体转移（皮肤、淋巴结、肺和肝）明显消退。其中两名患者皮肤转移的消退伴有红斑和 CD8+ T 细胞浸润，而非消退的病变缺乏 CD8+ T 细胞以及 Mage-3 mRNA 表达。这项研究证明了 DC“疫苗”经常扩展肿瘤特异性 CTL 并引发消退，甚至在晚期癌症中也是如此，此外，还为 CD8+ CTL-肿瘤细胞原位相互作用以及因缺乏肿瘤抗原表达而逃逸提供了证据。
Dendritic cells (DCs) are considered to be promising adjuvants for inducing immunity to cancer. We used mature, monocyte-derived DCs to elicit resistance to malignant melanoma. The DCs were pulsed with Mage-3A1 tumor peptide and a recall antigen, tetanus toxoid or tuberculin. 11 far advanced stage IV melanoma patients, who were progressive despite standard chemotherapy, received five DC vaccinations at 14-d intervals. The first three vaccinations were administered into the skin, 3 × 106 DCs each subcutaneously and intradermally, followed by two intravenous injections of 6 × 106 and 12 × 106 DCs, respectively. Only minor (less than or equal to grade II) side effects were observed. Immunity to the recall antigen was boosted. Significant expansions of Mage-3A1–specific CD8+ cytotoxic T lymphocyte (CTL) precursors were induced in 8/11 patients. Curiously, these immune responses often declined after the intravenous vaccinations. Regressions of individual metastases (skin, lymph node, lung, and liver) were evident in 6/11 patients. Resolution of skin metastases in two of the patients was accompanied by erythema and CD8+ T cell infiltration, whereas nonregressing lesions lacked CD8+ T cells as well as Mage-3 mRNA expression. This study proves the principle that DC “vaccines” can frequently expand tumor-specific CTLs and elicit regressions even in advanced cancer and, in addition, provides evidence for an active CD8+ CTL–tumor cell interaction in situ as well as escape by lack of tumor antigen expression.