Personalized‐induced neural stem cell therapy: Generation, transplant, and safety in a large animal model

Abstract

In this study, we take an important step toward clinical translation by generating the first canine-induced neural stem cells (iNSCs). We explore key aspects of scale-up, persistence, and safety of personalized iNSC therapy in autologous canine surgery models. iNSCs are a promising new approach to treat aggressive cancers of the brain, including the deadly glioblastoma. Created by direct transdifferentiation of fibroblasts, iNSCs are known to migrate through the brain, track down invasive cancer foci, and deliver anticancer payloads that significantly reduce tumor burden and extend survival of tumor-bearing mice. Here, skin biopsies were collected from canines and converted into the first personalized canine iNSCs engineered to carry TNFα-related apoptosis-inducing ligand (TRAIL) and thymidine kinase (TK), as well as magnetic resonance imaging (MRI) contrast agents for in vivo tracking. Time-lapse analysis showed canine iNSCs efficiently migrate to human tumor cells, and cell viability assays showed both TRAIL and TK monotherapy markedly reduced tumor growth. Using intraoperative navigation and two delivery methods to closely mimic human therapy, canines received autologous iNSCs either within postsurgical cavities in a biocompatible matrix or via a catheter placed in the lateral ventricle. Both strategies were well tolerated, and serial MRI showed hypointense regions at the implant sites that remained stable through 86 days postimplant. Serial fluid sample testing following iNSC delivery showed the bimodal personalized therapy was well tolerated, with no iNSC-induced abnormal tissue pathology. Overall, this study lays an important foundation as this promising personalized cell therapy advances toward human patient testing.

Glioblastoma Multiforme—A Look at the Past and a Glance at the Future

“…Effector molecules that have been used to regulate tumor growth include tumor necrosis factor apoptosis-inducing ligand (TRAIL), interferons ( / ), interleukins (ILs), and single-chain antibodies [ 59 , 60 ]. The antitumor effects of SCs expressing TRAIL have been extensively studied in GBM [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. TRAIL is a pro-apoptotic ligand that binds to death receptor (DR) 4 and 5 on cancer cells.…”

“…Though TRAIL stem cell-based therapies have shown to be efficacious in small-animal models, more clinically relevant models are warranted to determine their clinical utility. In an attempt to explore personalized, induced neural stem cell therapy for GBM, Bomba et al generated, transplanted and investigated the safety of iNSCs in a canine model [ 68 ]. Interestingly, pathology findings concluded no signs of abnormal pathology post-mortem and in vitro studies revealed that canine iNSC-sTR maintained their tumoritropic migratory properties and tumor killing capability.…”

“…Several in vivo preclinical studies have shown the clinical feasibility of NSCs and MSCs expressing HSV-TK for the treatment of GBM [ 70 , 71 , 72 ]. Bomba et al have also demonstrated the generation and safety of autologous, canine-derived NSCs expressing HSV-TK [ 68 ].…”

“…The use of biodegradable scaffolds to deliver cytotoxic SCs can prolong their residence time within the resection cavity, which can ultimately enhance anticancer efficacy. Several natural and synthetic polymer-based systems have demonstrated the ability to successfully encapsulate SCs, improve SC persistence, and enhance efficacy of cytotoxic SC therapy for post-surgical GBM [ 68 , 85 , 86 , 87 , 88 ]. Given the advantages of cell-laden polymeric constructs for post-surgical GBM, development of injectable polymeric gels that (1) can form implants in situ in response to physiological temperature and/or pH and (2) can be fine-tuned via crosslinking mechanisms to control biomaterial properties and stem cell release can further increase SC retainability and efficacy.…”

Cell-Based Therapy for the Treatment of Glioblastoma: An Update from Preclinical to Clinical Studies

“…Induced neural stem cells (iNSCs), cells that undergo transdifferentiation from the patients’ skin, are used as drug carriers with an innate tropism to neural cells including GB [ 127 ]. These cell derivatives can be genetically engineered to express cytotoxic proteins, which aid in cancer destruction as the cells will naturally migrate towards the cancer-invading area [ 127 ]. The iNSCs could carry therapeutic agents such as TNF α, and thymidine kinase [ 127 ].…”