肿瘤细胞治疗研究
英文原题：Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues.
胃肠道癌症（GICs）和神经内分泌肿瘤（NETs）在转移后往往对治疗耐药。
胃肠道肿瘤（GICs）和神经内分泌肿瘤（NETs）在转移后往往对治疗耐药。使用嵌合抗原受体（CAR）T细胞的过继细胞疗法虽然在治疗白血病方面效果显著，但在GICs和NETs等实体瘤中尚待开发。在此，我们分离了一种来源于美洲驼的纳米抗体VHH1，并发现它结合在GICs和NETs中上调的细胞表面黏附蛋白CDH17上。VHH1-CAR T细胞（CDH17CARTs）以CDH17依赖的方式杀伤人和小鼠肿瘤细胞。CDH17CARTs在肿瘤异种移植或自发小鼠模型中清除了表达CDH17的NETs以及胃、胰腺和结直肠癌。值得注意的是，CDH17CARTs不攻击同样表达CDH17的正常肠上皮细胞而造成毒性，这可能是因为CDH17仅定位于正常肠上皮细胞之间的紧密连接处。因此，CDH17代表了一类此前未被充分认识的肿瘤相关抗原，其在健康组织中被“遮蔽”而免受CAR T细胞攻击，从而可用于开发更安全的癌症免疫疗法。
Gastrointestinal cancers (GICs) and neuroendocrine tumors (NETs) are often refractory to therapy after metastasis. Adoptive cell therapy using chimeric antigen receptor (CAR) T cells, though remarkably efficacious for treating leukemia, is yet to be developed for solid tumors such as GICs and NETs. Here we isolated a llama-derived nanobody, VHH1, and found that it bound cell surface adhesion protein CDH17 upregulated in GICs and NETs. VHH1-CAR T cells (CDH17CARTs) killed both human and mouse tumor cells in a CDH17-dependent manner. CDH17CARTs eradicated CDH17-expressing NETs and gastric, pancreatic and colorectal cancers in either tumor xenograft or autochthonous mouse models. Notably, CDH17CARTs do not attack normal intestinal epithelial cells, which also express CDH17, to cause toxicity, likely because CDH17 is localized only at the tight junction between normal intestinal epithelial cells. Thus, CDH17 represents a class of previously unappreciated tumor-associated antigens that is 'masked' in healthy tissues from attack by CAR T cells for developing safer cancer immunotherapy.
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