Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer
Edited by Kornelia Polyak, Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA; received July 7, 2021; accepted November 15, 2021, by Editorial Board Member Anton Berns
Significance
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.
Abstract
Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood–brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.
Data Availability
All study data are included in the article and/or SI Appendix.
Acknowledgments
We thank Dr. Dihua Yu (MD Anderson Cancer Center) for providing BT474-Br cells. We also thank Yu Han, Aurora Lopez-Rosas, and Northwestern University animal facility for technical assistance. This work was supported by NIH Grants R35CA197725, R01NS093903 (M.S.L.), 1R01NS115955-01 (M.S.L. and J.M.), R33NS101150, R01NS106379 (I.V.B.), and R37CA258426 (C.L.-C.).
Supporting Information
Appendix 01 (PDF)
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Movie S1.
Migration of LM008-HER2Ab NSCs towards HER2+ brain metastatic BT474-Br tumor cells. Wound healing assays were performed by plating 7.104 BT474-Br and LM008-HER2Ab NSCs in different chambers of the cell culture insert (ibidi, Munich, Germany; www.ibidi.de). The cell culture insert was removed after 8 hours leaving a defined cell-free gap of 500 μm. Images were taken at 10X magnification every 5 minutes during 24 hours. BT474-Br tumor cells are represented in the left, and migrating LM008-HER2Ab NSCs are represented in the right.
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Copyright © 2021 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Data Availability
All study data are included in the article and/or SI Appendix.
Submission history
Accepted: November 15, 2021
Published online: December 30, 2021
Published in issue: January 5, 2022
Keywords
Acknowledgments
We thank Dr. Dihua Yu (MD Anderson Cancer Center) for providing BT474-Br cells. We also thank Yu Han, Aurora Lopez-Rosas, and Northwestern University animal facility for technical assistance. This work was supported by NIH Grants R35CA197725, R01NS093903 (M.S.L.), 1R01NS115955-01 (M.S.L. and J.M.), R33NS101150, R01NS106379 (I.V.B.), and R37CA258426 (C.L.-C.).
Notes
This article is a PNAS Direct Submission. K.P. is a guest editor invited by the Editorial Board.
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The authors declare no competing interest.
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Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer, Proc. Natl. Acad. Sci. U.S.A.
119 (1) e2112491119,
https://doi.org/10.1073/pnas.2112491119
(2022).
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