Preclinical Activity of Embryonic Annexin A2-Specific Chimeric Antigen Receptor T Cells Against Ovarian Cancer
Preclinical Activity of Embryonic Annexin A2-Specific Chimeric Antigen Receptor T Cells Against Ovarian Cancer
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DOI：
10.3390/ijms21020381
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发表时间：
2020-01-02
影响因子：
5.6
通讯作者：
Choo, Andre
中科院分区：
文献类型：
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作者：
Leong, Leonard;Heng Liang Tan;Choo, Andre
嵌合抗原受体（汽车）已在B细胞恶性肿瘤中取得临床成功，但缺乏潜在靶点限制了其更广泛的临床应用，尤其是在实体瘤中。在这里，我们描述了一种抗膜联蛋白A2 CAR（CAR（2448））的开发，该CAR来源于一种被发现对上皮性卵巢癌细胞系具有活性的抗体。通过实时细胞毒性试验，基于针对卵巢癌（OC）细胞系的体外细胞毒性活性优化了CAR（2448）的间隔区长度。较长的间隔CAR（2448）L T细胞表现出显著的效应子活性，诱导炎性细胞因子释放和针对OC细胞系的细胞毒性。此外，CAR（2448）L-BBz T细胞在体内OC异种移植物模型中诱导增强的存活，并使肿瘤体积减小76.6%。我们对CAR（2448）的临床前研究表明，它有潜力满足卵巢癌治疗新策略的未满足需求。
Chimeric antigen receptors (CARs) have found clinical success in B cell malignancies, but a dearth of potential targets limits their wider clinical application, especially in solid tumours. Here, we describe the development of an anti-annexin A2 CAR, CAR(2448), derived from an antibody found to have activity against epithelial ovarian cancer cell lines. The spacer length of CAR(2448) was optimised based on in vitro cytotoxic activity against ovarian cancer (OC) cell lines via a real-time cytotoxicity assay. The longer spacer CAR(2448)L T cells exhibit significant effector activity, inducing inflammatory cytokine release and cytotoxicity against OC cell lines. Furthermore, CAR(2448)L-BBz T cells induced enhanced survival in an in vivo OC xenograft model and reduced tumour volume by 76.6%. Our preclinical studies of CAR(2448) suggest its potential for the unmet need of novel strategies for the treatment of ovarian cancer.