A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four α-fetoprotein peptides
A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four α-fetoprotein peptides
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DOI：
10.1158/1078-0432.ccr-05-2856
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发表时间：
2006-05-01
影响因子：
11.5
通讯作者：
Economou, JS
中科院分区：
文献类型：
--
作者：
Butterfield, LH;Ribas, A;Economou, JS
甲胎蛋白(AFP)是胎儿肝脏高水平表达的一种自身蛋白，但在出生时被转录抑制。AFP在肝细胞癌中表达上调，活动期疾病患者的血浆水平可能高达1 mg/ml。我们以前从人AFP中鉴定出四个免疫优势的HLA-A*0201限制性多肽[hAFP(137-145)(PLFQVPEPV)、hAFP(158-166)(FMNKFIYEI)、hAFP(325-334)(GLSPNLNRFL)和hAFP(542-550)(GVALQTMKQ)]，它们能在体外刺激健康供者外周血淋巴细胞的特异性T细胞反应。我们进行了一项I/II期临床试验，对AFP阳性的肝细胞癌患者用冲击自体树突状细胞(DC)的四种AFP多肽皮内接种三次，每两周免疫一次。将贴壁的外周血单个核细胞与粒-巨噬细胞集落刺激因子和白介素4共同培养7d，制备DC。16名受试者入选，10名患者接受治疗。在AFP多肽/DC免疫前、免疫期间和免疫后分离外周血淋巴细胞，用MHC四聚体和干扰素-γELISPOT方法进行体外检测。10名受试者中有6名通过MHC四聚体将疫苗后有统计学意义的AFP特异性T细胞水平扩大到至少一种多肽。此外，在10名受试者中，有6人在接种后通过ELISPOT增加了产生AFP特异性T细胞对至少一种多肽的反应。我们得出结论，即使在循环中AFP抗原水平较高的环境中，人类T细胞在注射AFP多肽冲击的DC后仍能够对AFP自身抗原产生应答。
alpha-Fetoprotein (AFP) is a self protein expressed by fetal liver at high levels, but is transcriptionally repressed at birth. AFP is up-regulated in hepatocellular carcinomas, and patients with active disease could have plasma levels as high as 1 mg/mL. We previously identified four immunodominant HLA-A*0201-restricted peptides [hAFP(137-145) (PLFQVPEPV), hAFP(158-166) (FMNKFIYEI), hAFP(325-334) (GLSPNLNRFL), and hAFP(542-550) (GVALQTMKQ)] derived from human AFP that could stimulate specific T cell responses in healthy donor peripheral blood lymphocytes in vitro. We conducted a phase I/II clinical trial in which HLA-A*0201 patients with AFP-positive hepatocellular carcinoma were immunized with three biweekly intradermal vaccinations of the four AFP peptides pulsed onto autologous dendritic cells (DC). DCs were prepared from adherent peripheral blood mononuclear cells cultured with granulocyte-macrophage colony-stimulating factor and interleukin-4 for 7 days. Sixteen subjects were enrolled and 10 were treated. Peripheral blood lymphocytes were isolated from these patients before, during, and after AFP peptide/DC immunization and were tested ex vivo with MHC tetramer and IFN gamma ELISPOT analysis. Six of 10 subjects expanded statistically significant levels of AFP-specific T cells postvaccine to at least one peptide by MHC tetramer. Also, 6 of 10 subjects increased IFN gamma producing AFP-specific T cell responses to at least one of the peptides postvaccination, by ELISPOT We conclude that the human T cell repertoire is capable of responding to the AFP self antigen after the administration of AFP peptide-pulsed DC even in an environment of high circulating levels of this oncofetal antigen.