T cells expressing VHH-directed oligoclonal chimeric HER2 antigen receptors: Towards tumor-directed oligoclonal T cell therapy
T cells expressing VHH-directed oligoclonal chimeric HER2 antigen receptors: Towards tumor-directed oligoclonal T cell therapy
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DOI：
10.1016/j.bbagen.2013.09.029
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发表时间：
2014-01-01
影响因子：
3
通讯作者：
Moghimi，S. Moein
中科院分区：
文献类型：
--
作者：
Jamnani，Fatemeh Rahimi;Rahbarizadeh，Fatemeh;Moghimi，S. Moein
利用源自抗体的表达嵌合抗原受体（CARs）的工程化T细胞进行过继细胞治疗是一种很有前途的癌症免疫治疗策略。然而，一些不成功的试验强调需要替代传统结合域和更好的共刺激内结构域组合来构建CAR，以提高工程T细胞的效应功能。Camelid单域抗体（Camelid single-domain antibody, VHHs）是最小的单域抗体，具有很强的靶向car -工程T细胞的能力。方法：我们开发了一种方法来产生含有抗her2 VHH作为靶向片段的CAR的基因工程Jurkat T细胞。从免疫骆驼文库中，选择5个VHH克隆作为一组寡克隆抗her2 VHH，它们具有不同的结合能力，并将它们连接到CD28-CD3ζ和CD28-OX40-CD3ζ信号内域。观察Jurkat T细胞VHH-CARs的表达及细胞功能。结果寡克隆工程T细胞的增殖、细胞因子分泌和细胞毒性均高于单个vhh - car工程Jurkat T细胞。结论将寡克隆vhs优越的靶向能力与第三代CAR结合，可显著提高工程化T细胞的功能。抗原特异性定向寡克隆T细胞是另一种有希望的，但更安全的对抗肿瘤细胞的系统。
BackgroundAdoptive cell therapy with engineered T cells expressing chimeric antigen receptors (CARs) originated from antibodies is a promising strategy in cancer immunotherapy. Several unsuccessful trials, however, highlight the need for alternative conventional binding domains and the better combination of costimulatory endodomains for CAR construction to improve the effector functions of the engineered T cells. Camelid single-domain antibodies (VHHs), which are the smallest single domain antibodies, can endow great targeting ability to CAR-engineered T cells.MethodsWe have developed a method to generate genetically engineered Jurkat T cells armed with a CAR comprising the anti-HER2 VHH as targeting moiety. From an immune camel library, five VHH clones were selected as a set of oligoclonal anti-HER2 VHHs that exhibited diverse binding abilities and joined them to CD28-CD3ζ and CD28-OX40-CD3ζ signaling endodomains. Jurkat T cells expression of VHH-CARs and cell functions were evaluated.ResultsThe oligoclonal engineered T cells showed higher proliferation, cytokine secretion and cytotoxicity than each individual VHH-CAR-engineered Jurkat T cells.ConclusionsThe combination of superior targeting ability of oligoclonal VHHs with the third generation CAR can substantially improve the function of engineered T cells.General significanceAntigen-specific directed oligoclonal T cells are alternatively promising, but safer systems, to combat tumor cells.