Neural stem cells (NSCs) are ideal recruits for search-and-destroy missions in the brain. They have an innate ability to home in on cancer cells, and they can be engineered to release therapeutic agents. However, they can be hard to obtain from patients. And if they are called up from donors, NSCs bring the risk of adverse immune reactions and other complications. A safer alternative is to put some skin in the game—the patient’s own skin, that is.
Human skin cells can be reprogrammed to become NSCs. Also, these cells can be engineered to secrete a prodrug-activating protein. Ultimately, these cells are compatible with patient tissue but hostile toward brain tumors, report scientists from the University of North Carolina at Chapel Hill. These scientists recently completed a study demonstrating that induced human NSCs (iNSCs) can hunt down and kill human brain cancer.
The scientists provided detailed findings February 1 in the journal Science Translational Medicine, in an article entitled, “Tumor-Homing Cytotoxic Human Induced Neural Stem Cells for Cancer Therapy.” The article describes a critical step toward clinical trials—and a real treatment.
The transdifferentiation process used by the scientists took only 4 days to complete. This kind of speed is necessary, the scientists indicated, because they have in mind generating iNSCs quickly enough to treat patients afflicted with glioblastoma (GBM), a common and aggressive brain cancer. For GBM patients, median survival is less than 18 months, and a chance of surviving beyond 2 years is just 30%.
“Speed is essential,” said Shawn Hingtgen, Ph.D., an assistant professor who led the UNC-Chapel Hill team. “It used to take weeks to convert human skin cells to stem cells. But brain cancer patients don't have weeks and months to wait for us to generate these therapies. The new process we developed to create these stem cells is fast enough and simple enough to be used to treat a patient.”
In the current study, the scientists engineered the NSCs they generated to deliver two different types of therapies. The scientists also demonstrated that these engineered cells could infiltrate and effectively treat brain tumors in multiple mouse models.
“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,” wrote the authors. “Time-lapse motion analysis showed that h-iNSCTE rapidly migrated to human GBM cells and penetrated human GBM spheroids.”
“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,” the authors continued. “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.”
Surgery, radiation, and chemotherapy are the standard of care for GBM, and that hasn't changed in three decades. In months, the tumor comes back in almost every single patient, invariably sending tiny tendrils out into the surrounding brain tissue. Drugs can't reach them, and surgeons can't see them, so it's almost impossible to remove all of the cancer, explained Ryan Miller, M.D., Ph.D., a co-author of the study and neuropathologist at UNC Hospitals and associate professor at the UNC School of Medicine.
“We desperately need something better,” said Hingtgen.
The key to Hingtgen's treatment is “skin flipping,” a technology for creating NSCs from skin cells that won Shinya Yamanaka, Ph.D., and Sir John Gurdon a Nobel Prize in 2012. The first step is to harvest fibroblasts—skin cells responsible for producing collagen and connective tissue—from the patient and reprogram those cells to become what are called iNSCs, which have an innate ability to home in on cancer cells in the brain.
But by themselves, stem cells can only find a tumor and bump up against it—not kill it—so the team had to engineer stem cells that could carry therapeutic agents that the cells can launch at the tumor to kill it.
Hingtgen's stem cells can carry a protein that activates an inert substance called a prodrug that is given to the patient. The cells can then generate a small halo of drug that is located just around the stem cell, rather than it being circulated throughout the patient's body, reducing unwanted side effects.
“We're 1 to 2 years away from clinical trials, but for the first time, we showed that our strategy for treating glioblastoma works with human stem cells and human cancers,” said Hingtgen. “This is a big step toward a real treatment—and making a real difference.”