新規エクソソーム標的免疫療法薬によるHer2陽性乳がん治療
Xinliang Lu1, Weiyi Yuan2, Xianchang Zeng3
1Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
Abstract:
Trastuzumab profoundly improves outcomes of Her2+ breast cancer (BC) patients, but eventual drug resistance is inevitable. Therefore, new treatment options are urgently needed. Here, we modify extracellular vesicles (EVs) with a Her2 single-chain variable fragment of trastuzumab (EVs/Her2-scFv) to target Her2+ BC and found that EVs/Her2-scFv inhibit human Her2+ orthotopic BC comparable to trastuzumab and also uniquely suppress brain metastasies. Moreover, EVs/Her2-scFv loaded with rabeprazole (EVs/Her2-scFv/Rabe) effectively improve tumor immunosuppressive microenvironment and abnormal vasculature of Her2+ BC by reducing tumor EVs. When further anchored with CD8+ T cell chemotactic CXCL9, CXCL9-loaded EVs/Her2-scFv/Rabe (EVs/Her2-scFv/CXCL9/Rabe) facilitate CD8+ T cell recruitment and subsequent activation, thereby exhibiting immunotherapeutic effects on mouse Her2+ BC. In BC patient-derived tumor organoids (PDOs) and peripheral blood mononuclear cell coculture systems, EVs/Her2-scFv/CXCL9/Rabe limit PDO growth by blocking Her2 signaling and activating CD8+ T cells. Besides, EVs/Her2-scFv/CXCL9/Rabe are low-immunogenic with biosafety. Altogether, EVs/Her2-scFv/CXCL9/Rabe hold high potential in Her2+ BC therapy.
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