{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T19:46:34Z","timestamp":1788637594585,"version":"build-2803163510"},"reference-count":52,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"unspecified","delay-in-days":9,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005351","name":"Neurosurgery Research and Education Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100005351","id-type":"DOI","asserted-by":"publisher"}]},{"name":"BioNTech SE, Mainz, Germany","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["318346496, SFB1292\/2 TPQ1, TP22"],"award-info":[{"award-number":["318346496, SFB1292\/2 TPQ1, TP22"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Emily Whitehead Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,9,7]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2009and 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-\u03b3c\u2013\/\u2013 (NSG) mouse models bearing orthotopic xenograft tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  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