CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: Solid tumors comprise approximately 60% of all pediatric cancers. Relapsed or refractory tumors of the central nervous system (CNS), such as atypical teratoid/rhabdoid tumors (AT/RTs), are the leading cause of death in children with cancer. Claudin 6 (CLDN6)-specific chimeric antigen receptor (CAR) T cells have demonstrated activity in preclinical and clinical studies in various solid adult cancers. However, the suitability of CLDN6 as a target in pediatric tumors and their susceptibility to CAR T-cell therapy has yet to be established. This study aimed to evaluate the suitability of CLDN6 as a target for CAR T-cell therapy of pediatric solid tumors. METHODS: Immunohistochemical CLDN6 expression was assessed in fetal normal tissues (n=91), pediatric normal tissues (n=157), and two sets of pediatric tumor tissues (n=527 and n=49) using a combined score that includes the percentage of stained cells with a 4-point intensity scale (0 to 3+). The antitumor activity of CLDN6 RNA-transduced CAR T cells against AT/RT cell lines was assessed with in vitro assays and in immunodeficient NOD-SCID- c-/- (NSG) mouse models bearing orthotopic xenograft tumors. RESULTS: Membranous CLDN6 expression, as detected by immunohistochemistry, was widely observed in fetal tissues but was absent in almost all non-malignant pediatric tissues, except for very rare, scattered cells with 1+ to 2+ intensity in kidney, pancreas, pituitary, and salivary gland tissues. Membranous CLDN6 expression was frequently detected in a subset of the pediatric tumor entities, including germ cell tumors (93% of samples with CLDN6-positive cells), nephroblastoma (64%), extracranial malignant rhabdoid tumors (50%), and AT/RTs (39%). In CLDN6-positive samples, CLDN6 was generally expressed with 2+ or 3+ intensity in substantial proportions of the cancer cells. Strong CLDN6 expression was also detected in single samples of hepatoblastoma, Ewing sarcoma/other embryonal tumors, and osteosarcoma.In experimental models, CLDN6-CAR T cells led to antigen-specific killing of endogenously CLDN6-expressing AT/RT cell lines in vitro and exhibited potent and specific antitumor activity in mice bearing orthotopic CLDN6-expressing AT/RT xenograft tumors. CONCLUSIONS: These results support CLDN6 as an oncofetal cell-surface antigen that may be suitable for CAR T-cell targeting in pediatric solid tumors, including those of the CNS.