肿瘤细胞治疗研究
英文原题：Chimeric antigen receptor T cell targeting CD44E variant in HCC holds therapeutic potential.
嵌合抗原受体（CAR）T细胞疗法在血液系统恶性肿瘤中取得了显著成功。
嵌合抗原受体（CAR）T细胞疗法在血液系统恶性肿瘤中取得了显著成功。然而，其在肝细胞癌（HCC）中的疗效仍然有限。一个主要挑战是缺乏可靠的肿瘤抗原供CAR T细胞识别。CD44E是CD44跨膜蛋白的一种独特可变剪接（AS）变体，与邻近非肿瘤肝组织相比，其在HCC肿瘤中高表达，有望成为潜在的治疗靶点。在此，我们成功开发了一种来源于S431杂交瘤克隆的CD44E特异性单克隆抗体。利用该抗体，我们证实了CD44E蛋白在患者来源的HCC细胞系、类器官和原发肿瘤组织中的表达。通过整合S431抗体的单链可变片段（scFv），设计了第二代CAR。这些抗CD44E CAR T细胞在体外和体内模型中均表现出对CD44阳性HCC细胞的特异性细胞毒性，并且重要的是，在动物模型中未在重要器官中诱导可检测的毒性。我们的研究结果表明，靶向CD44E的CAR T细胞疗法可能代表一种有前景的HCC治疗方法。
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies. However, its efficacy in hepatocellular carcinoma (HCC) remains limited. One major challenge is the lack of reliable tumor antigens for CAR T cell recognition. CD44E, a unique alternative splicing (AS) variant of CD44 transmembrane protein that is highly expressed in HCC tumors compared to adjacent non-tumoral liver tissues, holds promise as a potential therapeutic target. Here, we successfully developed a CD44E-specific monoclonal antibody derived from the S431 hybridoma clone. Using this antibody, we confirmed CD44E protein expression in patient-derived HCC cell lines, organoids, and primary tumor tissues. A second-generation CAR was designed by incorporating the single-chain variable fragment (scFv) of the S431 antibody. These anti-CD44E CAR T cells exhibited specific cytotoxicity against CD44-positive HCC cells in both in vitro and in vivo models and importantly, did not induce detectable toxicity in vital organs in animal models. Our findings suggested that CD44E-targeting CAR T cell therapy might represent a promising therapeutic approach for HCC treatment.
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