Tumor-homing cytotoxic human induced neural stem cells for cancer therapy.
Engineered neural stem cells (NSCs) are a promising approach to treating glioblastoma (GBM). The ideal NSC drug carrier for clinical use should be easily isolated and autologous to avoid immune rejection. We transdifferentiated (TD) human fibroblasts into tumor-homing early-stage induced NSCs (h-iNSCTE), engineered them to express optical reporters and different therapeutic gene products, and assessed the tumor-homing migration and therapeutic efficacy of cytotoxic h-iNSCTEin patient-derived GBM models of surgical and nonsurgical disease. Molecular and functional analysis revealed that our single-factor SOX2 TD strategy converted human skin fibroblasts into h-iNSCTEthat were nestin+and expressed pathways associated with tumor-homing migration in 4 days. Time-lapse motion analysis showed that h-iNSCTErapidly migrated to human GBM cells and penetrated human GBM spheroids, a process inhibited by blockade of CXCR4. Serial imaging showed that h-iNSCTEdelivery of the proapoptotic agent tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) reduced the size of solid human GBM xenografts 250-fold in 3 weeks and prolonged median survival from 22 to 49 days. Additionally, h-iNSCTEthymidine kinase/ganciclovir enzyme/prodrug therapy (h-iNSCTE-TK) reduced the size of patient-derived GBM xenografts 20-fold and extended survival from 32 to 62 days. Mimicking clinical NSC therapy, h-iNSCTE-TK therapy delivered into the postoperative surgical resection cavity delayed the regrowth of residual GBMs threefold and prolonged survival from 46 to 60 days. These results suggest that TD of human skin into h-iNSCTEis a platform for creating tumor-homing cytotoxic cell therapies for cancer, where the potential to avoid carrier rejection could maximize treatment durability in human trials.
Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Juli R
JR
Bagó
Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Onyi
O
Okolie
UNC Human Pluripotent Stem Cell Core Facility, Department of Genetics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Raluca
R
Dumitru
Department of Neurosurgery, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Matthew G
MG
Ewend
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Joel S
JS
Parker
Department of Cellular and Physiological Sciences, Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Ryan Vander
RV
Werff
Department of Cellular and Physiological Sciences, Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
T Michael
TM
Underhill
Division of Neuropathology and Department of Pathology and Laboratory Medicine, Department of Neurology and Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Ralf S
RS
Schmid
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Division of Neuropathology and Department of Pathology and Laboratory Medicine, Department of Neurology and Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
C Ryan
CR
Miller
Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. hingtgen@email.unc.edu.|Department of Neurosurgery, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Shawn D
SD
Hingtgen
D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D002465:Cell Movement; D054338:Cell Transdifferentiation; D016503:Drug Delivery Systems; D005347:Fibroblasts / Q000166:cytology; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000637:transplantation; D012867:Skin / Q000166:cytology; D018874:Spheroids, Cellular; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D053221:TNF-Related Apoptosis-Inducing Ligand