肿瘤细胞治疗研究
英文原题：New CEACAM-targeting 2A3 single-domain antibody-based chimeric antigen receptor T-cells produce anticancer effects in vitro and in vivo.
New CEACAM-targeting 2A3 single-domain antibody-based chimeric antigen receptor T-cells produce anticancer effects in vitro and in vivo.
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最近，一种突破性的免疫治疗策略——嵌合抗原受体（CAR）T细胞已被引入血液肿瘤学领域。然而，要将这种新型治疗方法应用于实体瘤，必须首先确定所选肿瘤中合适的分子靶点。CEACAM家族蛋白参与多种恶性肿瘤的进展，包括胰腺癌和乳腺癌，是抗癌治疗中具有吸引力的靶点。
在本研究中，我们使用一种新型的靶向CEACAM的2A3单域抗体为基础的CAR-T 细胞，在体外和动物模型中评估其抗肿瘤特性。最初，2A3抗体被报道靶向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高表达的人细胞系具有激活作用和高细胞毒性，提示该抗体具有交叉反应性。
此外，在BxPC-3异种移植模型中进行的体内实验表明，2A3-CAR-T 细胞在早期和晚期干预治疗方案中均对胰腺癌异种移植瘤表现出高效性。
我们的结果首次表明，新型2A3 sdAb为基础的CAR-T 细胞对CEACAM5和CEACAM6分子具有增强的靶向能力。这些结果强烈支持进一步开发2A3-CAR-T 细胞作为治疗CEACAM5/6过表达癌症的潜在策略。
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.
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