Feng Zijie, He Xin, Zhang Xuyao, Wu Yuan, Xing Bowen, Knowles Alison, Shan Qiaonan, Miller Samuel, Hojnacki Taylor, Ma Jian, Katona Bryson W, Gade Terence P F, Siegel Don L, Schrader Jörg, Metz David C, June Carl H, Hua Xianxin
Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Division of Gastroenterology and Hepatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Nat Cancer. 2022 May;3(5):581-594. doi: 10.1038/s43018-022-00344-7. Epub 2022 Mar 21.
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.
胃肠道癌（GICs）和神经内分泌肿瘤（NETs）转移后通常对治疗具有抗性。嵌合抗原受体（CAR）T细胞过继性细胞疗法虽然在治疗白血病方面效果显著，但尚未用于治疗诸如GICs和NETs等实体瘤。在此，我们分离出一种源自羊驼的纳米抗体VHH1，并发现它能结合在GICs和NETs中上调的细胞表面粘附蛋白CDH17。VHH1-CAR T细胞（CDH17CARTs）以依赖CDH17的方式杀伤人和小鼠肿瘤细胞。在肿瘤异种移植或原位小鼠模型中，CDH17CARTs根除了表达CDH17的NETs以及胃癌、胰腺癌和结直肠癌。值得注意的是，CDH17CARTs不会攻击同样表达CDH17的正常肠上皮细胞而导致毒性，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代表了一类以前未被认识的肿瘤相关抗原，其在健康组织中“隐藏”起来，免受CAR T细胞攻击，从而有望开发出更安全的癌症免疫疗法。
