PDF(Pubmed)
Abstract：
Recently, a breakthrough immunotherapeutic strategy of chimeric antigen receptor (CAR) T-cells has been introduced to hematooncology. However, to apply this novel treatment in solid cancers, one must identify suitable molecular targets in the tumors of choice. CEACAM family proteins are involved in the progression of a range of malignancies, including pancreatic and breast cancers, and pose attractive targets for anticancer therapies. In this work, we used a new CEACAM-targeted 2A3 single-domain antibody-based chimeric antigen receptor T-cells to evaluate their antitumor properties in vitro and in animal models. Originally, 2A3 antibody was reported to target CEACAM6 molecule; however, our in vitro co-incubation experiments showed activation and high cytotoxicity of 2A3-CAR T-cells against CEACAM5 and/or CEACAM6 high human cell lines, suggesting cross-reactivity of this antibody. Moreover, 2A3-CAR T-cells tested in vivo in the BxPC-3 xenograft model demonstrated high efficacy against pancreatic cancer xenografts in both early and late intervention treatment regimens. Our results for the first time show an enhanced targeting toward CEACAM5 and CEACAM6 molecules by the new 2A3 sdAb-based CAR T-cells. The results strongly support the further development of 2A3-CAR T-cells as a potential treatment strategy against CEACAM5/6-overexpressing cancers.
摘要：
最近,嵌合抗原受体(CAR)T细胞的突破性免疫治疗策略已被引入血液肿瘤学.然而,将这种新的治疗方法应用于实体癌，必须在选择的肿瘤中确定合适的分子靶标。CEACAM家族蛋白参与一系列恶性肿瘤的进展，包括胰腺癌和乳腺癌，并为抗癌治疗提供有吸引力的目标。在这项工作中,我们使用一种新的CEACAM靶向的基于2A3单结构域抗体的嵌合抗原受体T细胞,在体外和动物模型中评估其抗肿瘤特性.最初,据报道，2A3抗体靶向CEACAM6分子；然而，我们的体外共孵育实验显示2A3-CAR-T细胞对CEACAM5和/或CEACAM6高人细胞系的活化和高细胞毒性，提示这种抗体的交叉反应性。此外，在BxPC-3异种移植物模型中体内测试的2A3-CART细胞在早期和晚期干预治疗方案中表现出对胰腺癌异种移植物的高疗效。我们的结果首次显示新的基于2A3sdAb的CART细胞对CEACAM5和CEACAM6分子的靶向增强。结果强烈支持2A3-CAR-T细胞作为针对CEACAM5/6过表达癌症的潜在治疗策略的进一步发展。
