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Brain metastases are among the most severe complications of systemic breast cancer, and overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer cells increases the incidence of brain metastases in patients. In this study, we engineered the human-derived, tumor cell tropic neural stem cells LM-NSC008 (LM008) to continuously secrete antibodies against HER2. These anti-HER2 antibodies impaired tumor cell proliferation by inhibiting the PI3K-Akt signaling pathway in HER2+ breast cancer cells in vitro. Importantly, our results demonstrate that the therapeutic combinatorial regimen consisting of LM-NSC008 anti-HER2 antibody-secreting cells and the HER2 kinase inhibitor tucatinib provide therapeutic benefit and prolong survival in preclinical models of HER2+ breast cancer brain metastases. ....

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