Research ArticleCancer

Tumor-homing cytotoxic human induced neural stem cells for cancer therapy

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Science Translational Medicine  01 Feb 2017:
Vol. 9, Issue 375, eaah6510
DOI: 10.1126/scitranslmed.aah6510

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Stem cells on a mission

Healthy neural stem cells can infiltrate and help treat brain tumors because they naturally migrate toward gliomas in response to chemotactic signals released by the tumor cells. Obtaining neural stem cells from a patient can be difficult, however, and donor stem cells pose a risk of immune rejection and other safety concerns. Bagó et al. have discovered a way to avoid these risks by taking normal human skin fibroblasts and transdifferentiating them into neural stem cells. The entire process took only 4 days to complete, yielding autologous patient-derived neural stem cells. The authors engineered these stem cells to deliver two different types of therapies and demonstrated their ability to infiltrate and effectively treat brain tumors in multiple mouse models.

Abstract

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-iNSCTE in 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-iNSCTE that were nestin+ and expressed pathways associated with tumor-homing migration in 4 days. Time-lapse motion analysis showed that h-iNSCTE rapidly migrated to human GBM cells and penetrated human GBM spheroids, a process inhibited by blockade of CXCR4. Serial imaging showed that h-iNSCTE delivery 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-iNSCTE thymidine 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-iNSCTE is 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.

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