Cytotoxic Engineered Induced Neural Stem Cells as an Intravenous Therapy for Primary Non-Small Cell Lung Cancer and Triple-Negative Breast Cancer

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Background: Converting human fibroblasts into personalized induced neural stem cells (hiNSCs) that actively seek out tumors and deliver cytotoxic agents is a promising approach for treating cancer. Herein, we provide the first evidence that intravenously-infused hiNSCs home to and suppress the growth of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). Methods: Migration of hiNSCs to NSCLC and TNBC in vitro was investigated using time-lapse motion analysis. In vivo, migration of intravenous hiNSCs to orthotopic NSCLC or TNBC was determined using bioluminescent imaging (BLI) and immunofluorescent post-mortem tissue analysis. In vitro, efficacy of hiNSCs releasing cytotoxic TRAIL (hiNSC-TRAIL) was monitored using kinetic imaging of co-cultures. Efficacy was determined in vivo by infusing hiNSC-TRAIL or control cells intravenously into mice bearing orthotopic NSCLC or TNBC and tracking changes in tumor volume using BLI. Safety was assessed by hematology, blood chemistry, and histology. Findings: hiNSCs migrated to both human NSCLC and human TNBC in vitro and co-localized with orthotopic NSCLC or TNBC tumors within 3 days and persisted through 14 days in vivo. In vitro, hiNSC-TRAIL therapy induced rapid killing of NSCLC and TNBC. In vivo, intravenous hiNSC-TRAIL therapy reduced human NSCLC and TNBC tumors 42% and 70%, respectively, and induced no significant changes in safety parameters through 28 days. Interpretation: Intravenous hiNSCs seek out and kill NSCLC and TNBC tumors, suggesting a potential new strategy for treating aggressive peripheral cancers. Funding Statement: This work was supported by Eshelman Institute for Innovation and the National Cancer Institute of the National Institutes of Health under Award Number F30CA243270. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Declaration of Interests: K.T.S. and S.D.H have an ownership interest in Falcon Therapeutics, Inc., which has licensed aspects of hiNSC technology from the University of North Carolina at Chapel Hill. C.K.A. has research funding from PUMA, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, and G1-Therapeutics. C.K.A. has compensated consulting roles from Genentech, Eisai, IPSEN, and Seattle Genetics with royalties from UpToDate, and Jones and Bartlett. A.R.M.S., W.J., J.R.B., A.V., S.A.M., and A.S.W., have no conflicts to disclose. Ethics Approval Statement: All experimental mouse protocols were previously approved by the Institutional Animal Care and Use Committees at the University of North Carolina -- Chapel Hill.