Generation and profiling of tumor-homing induced neural stem cells from the skin of cancer patients

Abstract Converting human fibroblasts into personalized induced neural stem cells (iNSCs) that actively seek out tumors and deliver cytotoxic agents is a highly promising approach for treating various types of cancer. However, the ability to generate iNSCs from the skin of cancer patients has not been explored. Here, we take an important step towards clinical application by generating iNSCs from skin biopsies of human patients undergoing treatment for the aggressive brain cancer, glioblastoma (GBM). We then utilized a panel of functional and genomic studies to investigate the efficacy and tumor-homing capacity of these patient-derived cells as well as genomic analysis to characterize the impact of interpatient variability on this personalized cell therapy. From the skin tissue biopsies, we established fibroblasts and transdifferentiated the cells into iNSCs. Genomic and functional testing revealed marked variability in growth rates, therapeutic agent production, and gene expression during fibroblast to iNSC conversion among patient lines. In vivo testing showed patient-derived iNSCs home to tumors, yet rates and expression of homing-related pathways varied among patients. Using surgical resection mouse models of invasive human CD133+ GBM cells and serial kinetic imaging, we found that “high performing” patient-derived iNSC lines reduced the volume of GBM cells 60-fold and extended survival from 28 to 45 days. Treatment with “low performing” patient lines had minimal effect on tumor growth, but the anti-tumor effect could be rescued by increasing the intra-cavity dose. Together, these data show for the first time that tumor-homing iNSCs can be generated from the skin of cancer patients and efficaciously suppress tumor growth. We also begin to define genetic markers that could be used to identify cells that will contain the most effective attributes for tumor homing and kill in human patients, including high gene expression of the semaphorin SEMA3B, which is known to be involved in neuronal cell migration. These studies should serve as an important guide towards clinical GBM therapy, where the personalized nature of optimized iNSC therapy has the potential to avoid transplant rejection and maximize treatment durability.