鉴定用于肝细胞癌免疫治疗的甲胎蛋白特异性T细胞受体

StephenW

Identification of α‐fetoprotein‐specific T‐cell receptors for hepatocellular carcinoma immunotherapy
Wei Zhu
Yibing Peng
Lan Wang
Yuan Hong
Xiaotao Jiang
Qi Li
Heping Liu
Lei Huang
Juan Wu
Esteban Celis
Todd Merchen
Edward Kruse
Yukai He
First published: 14 February 2018
https://doi.org/10.1002/hep.29844

Potential conflict of interest: Nothing to report.

Supported by a National Institutes of Health/National Cancer Institute grant (R01 CA168912, to Y.H.) and a Georgia Cancer Center grant (to Y.H., T.M., and E.K.).
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Abstract

Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T‐cell receptors (TCRs) specific for HCC‐associated antigens, such as α‐fetoprotein (AFP), can potentially redirect human T cells to specifically recognize and kill HCC tumor cells to achieve antitumor effects. In this study, using lentivector and peptide immunization, we identified a population of cluster of differentiation 8 (CD8) T cells in human leukocyte antigen (HLA)‐A2 transgenic AAD mice that recognized AFP158 epitope on human HCC cells. Adoptive transfer of the AFP158‐specific mouse CD8 T cells eradicated HepG2 tumor xenografts as large as 2 cm in diameter in immunocompromised nonobese diabetic severe combined immunodeficient gamma knockout (NSG) mice. We then established T‐cell hybridoma clones from the AFP158‐specific mouse CD8 T cells and identified three sets of paired TCR genes out of five hybridomas. Expression of the murine TCR genes redirected primary human T cells to bind HLA‐A2/AFP158 tetramer. TCR gene‐engineered human T (TCR‐T) cells also specifically recognized HLA‐A2+AFP+ HepG2 HCC tumor cells and produced effector cytokines. Importantly, the TCR‐T cells could specifically kill HLA‐A2+AFP+ HepG2 tumor cells without significant toxicity to normal primary hepatocytes in vitro. Adoptive transfer of the AFP‐specific TCR‐T cells could eradicate HepG2 tumors in NSG mice. Conclusion: We have identified AFP‐specific murine TCR genes that can redirect human T cells to specifically recognize and kill HCC tumor cells, and those AFP158‐specific TCRs have a great potential to engineer a patient's autologous T cells to treat HCC tumors. (Hepatology 2018).

StephenW

鉴定用于肝细胞癌免疫治疗的甲胎蛋白特异性T细胞受体
魏朱
彭一兵
兰王
袁宏
小涛江
齐力
刘和平
黄磊
吴娟
Esteban Celis
Todd Merchen
爱德华克鲁斯
Yukai He
首次发表：2018年2月14日
https://doi.org/10.1002/hep.29844

潜在的利益冲突：无需报告。

由美国国立卫生研究院/国家癌症研究所资助（R01 CA168912，Y.H。）和佐治亚州癌症中心资助（Y.H.，T.M。和E.K.）资助。
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肝细胞癌（HCC）是肝癌的主要形式，没有有效的治疗方法。用特异于HCC相关抗原（例如甲胎蛋白（AFP））的T细胞受体（TCR）进行遗传修饰可以潜在地重定向人T细胞以特异性识别和杀死HCC肿瘤细胞以实现抗肿瘤效果。在该研究中，使用慢病毒和肽免疫，我们在人白细胞抗原（HLA）-A2转基因AAD小鼠中鉴定了一群分化群8（CD8）T细胞，其识别人HCC细胞上的AFP158表位。过继转移AFP158特异性小鼠CD8 T细胞根除直径大至2cm的HepG2肿瘤异种移植物在免疫妥协的非肥胖糖尿病严重联合免疫缺陷性γ敲除（NSG）小鼠中。然后我们从AFP158特异性小鼠CD8 T细胞建立T细胞杂交瘤克隆，并从五个杂交瘤中鉴定出三组配对的TCR基因。鼠TCR基因的表达使原代人T细胞重定向以结合HLA-A2 / AFP158四聚体。 TCR基因工程人T（TCR-T）细胞还特异性识别HLA-A2 + AFP + HepG2 HCC肿瘤细胞并产生效应细胞因子。重要的是，TCR-T细胞可以特异性地杀死HLA-A2 + AFP + HepG2肿瘤细胞，而对体外正常的原代肝细胞没有显着的毒性。过继转移AFP特异性TCR-T细胞可以根除NSG小鼠中的HepG2肿瘤。结论：我们已经鉴定了AFP特异性鼠TCR基因，其可以重定向人T细胞以特异性识别和杀死HCC肿瘤细胞，并且那些AFP158特异性TCR具有很大的潜力来设计患者的自体T细胞来治疗HCC肿瘤。 （Hepatology 2018）。