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Therefore, we evaluated the dual\u2010targeting antitumor ability of these cells and confirmed their efficacy against lung adenocarcinoma. First, we evaluated EphB4 and EphA2 expression in samples from 74 patients with lung adenocarcinoma using immunohistochemistry. Next, EphB4 CAR\u2010T cells were generated via\n                    <jats:italic>piggyBac<\/jats:italic>\n                    \u2010mediated gene transfer, and their phenotype was evaluated. Subsequently, we conducted an antigen stimulation assay to assess the bispecificity of the EphB4 CAR\u2010T cells. Finally, the antitumor effects of EphB4 CAR\u2010T cells on lung adenocarcinoma cell lines were assessed. EphB4 and EphA2 positivity in lung adenocarcinoma samples was 93% and 100%, respectively. EphB4 CAR\u2010T cells were successfully generated with high CAR positivity and a high proportion of na\u00efve\/stem cell memory\u2010like T cells. In the antigen stimulation assay, the cells responded in an antigen\u2010specific manner after stimulation with both EphB4 and EphA2 proteins. In the co\u2010culture experiment, EphB4 CAR\u2010T cells significantly suppressed the growth of all four lung adenocarcinoma cell lines compared to mock\u2010T cells. In\u00a0vivo, mice treated with EphB4 CAR\u2010T cells displayed a significantly lower tumor burden than those treated with either CD19 CAR\u2010T cells or phosphate\u2010buffered saline. Additionally, mice treated with EphB4 CAR\u2010T cells survived significantly longer than those in the other groups. In conclusion, ligand\u2010based EphB4 CAR\u2010T cells are bispecific, targeting both EphB4 and EphA2. Furthermore, these cells exert significant antitumor effects against lung adenocarcinoma.\n                  <\/jats:p>","DOI":"10.1111\/cas.70397","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T08:15:16Z","timestamp":1776759316000},"page":"1724-1735","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bispecific Ligand\u2010Based EphB4 CAR\u2010T Cells Generated Using Ephrin\u2010B2 Show Potent Antitumor Activity Against Lung Adenocarcinoma"],"prefix":"10.1111","volume":"117","author":[{"given":"Hirotaka","family":"Kumeda","sequence":"first","affiliation":[{"name":"Division of General Thoracic Surgery, Department of Surgery Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2193-1184","authenticated-orcid":false,"given":"Koichi","family":"Hirabayashi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuji","family":"Mishima","sequence":"additional","affiliation":[{"name":"Division of General Thoracic Surgery, Department of Surgery Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Furui","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Fujioka","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Shinshu University School of Medicine  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Shinshu University Hospital  Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyuki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Shinshu University School of Medicine  Matsumoto Japan"},{"name":"Center for Advanced Research of Gene and Cell Therapy in Shinshu University (CARS) Shinshu University School of Medicine  Matsumoto Japan"},{"name":"A\u2010SEEDS Co., Ltd.  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