肿瘤细胞治疗研究
英文原题：Targeting Cancer-Associated Glycosylation for Adoptive T-cell Therapy of Solid Tumors.
嵌合抗原受体（CAR）T 细胞治疗改善了化疗耐药 B 细胞恶性肿瘤患者的结局。
嵌合抗原受体（CAR）T细胞疗法改善了化疗耐药B细胞恶性肿瘤患者的结局，但治疗实体瘤仍较困难，部分原因是肿瘤特异性细胞表面抗原表达具有异质性。本研究描述了一种完全人源CAR，可靶向分泌性上皮癌中的异常糖基化。研究使用高度特异性识别唾液酸化Thomsen-nouveau（STn）截短O-聚糖抗原的抗体，分析其在多种肿瘤组织中的表达。在相当比例的胃肠道癌症（包括胰腺癌）及妇科癌症（尤其卵巢癌和子宫内膜癌）中发现强表达。研究在体外和体内检测抗STn CAR-T细胞。该细胞在小鼠模型及原发性卵巢癌样本实验中均显示活性。小鼠模型中未见显著毒性，但在小鼠胃肠道组织的部分腔面发现STn表达。总之，这种完全人源抗STn CAR构建体在临床前肿瘤模型中显示良好活性，支持进一步在早期临床试验中评估。
Chimeric antigen receptor (CAR) T-cell therapy has improved outcomes for patients with chemotherapy-resistant B-cell malignancies. However, CAR T-cell treatment of patients with solid cancers has been more difficult, in part because of the heterogeneous expression of tumor-specific cell surface antigens. In this study, we describe the generation of a fully human CAR targeting altered glycosylation in secretory epithelial cancers. The expression of the target antigen-the truncated, sialylated O-glycan Sialyl-Thomsen-nouveau (STn) antigen-was studied with a highly STn-specific antibody across various different tumor tissues. Strong expression was found in a high proportion of gastrointestinal cancers, including pancreatic cancers, and in gynecologic cancers, in particular ovarian and endometrial tumors. T cells expressing anti-STn CAR were tested in vitro and in vivo. Anti-STn CAR T cells showed activity in mouse models, as well as in assays with primary ovarian cancer samples. No considerable toxicity was observed in mouse models although some intraluminal expression of STn was found in gastrointestinal mouse tissue. Taken together, this fully human anti-STn CAR construct shows promising activity in preclinical tumor models, supporting its further evaluation in early clinical trials.
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