Right Now | Vectored Vaccine
Using Cancer to Kill Cancer
Scientists dream of finding a cure for glioblastoma, a brutally aggressive type of brain tumor; few patients survive longer than 18 months after diagnosis. But preclinical research in the lab of professor of neurosurgery Khalid Shah could change that prognosis. Using immunotherapy, one of the most promising approaches to fighting cancer, Shah and his team have developed a novel vaccine that deploys engineered cancer cells to target and destroy tumors—and prevents them from returning.
Since 2006, Shah has worked to develop and test new therapies for brain cancers, including glioblastoma (GBM). But his work took on new urgency in 2018, when his father was diagnosed with this type of brain tumor. “He lasted only six weeks,” explains Shah, director of the Center for Stem Cell and Translational Immunotherapy at Brigham and Women’s Hospital. “His passing away has strengthened my resolve to find a cure for GBM.”
Solid tumors such as glioblastoma are notorious for evading treatments and making themselves invisible to the immune system. Shah wondered if it would be possible to counter such evasion by packaging treatment in live cancer cells, which have what he calls a “fascinating property”: they home to their sister cells and tumors, like bees following one another to the hive. “We said, ‘Why can’t we use the cancer itself?’ That is the only way to beat it because no other cells could match this migratory capability.” Most existing cell-based therapies for brain cancer use inactivated cancer cells, which can’t zero in on tumors. And live cancer cells are more likely than inactivated ones to have robust neoantigens, or new proteins that result from mutations in cancer cells, which provoke an anti-tumor immune response. “Once you inactivate the cell,” Shah says, a few might be retained, “but the neoantigens on the live cell are more pronounced.”
Shah’s team used gene-editing technology to modify the live cells for two new purposes. First, they knocked out a receptor on the surface of the cells in order to make them invulnerable to a potent cancer-killing substance known as interferon beta. With that resistance in place, they next engineered the cells to release interferon beta and destroy other tumor cells. Second, they altered the cell to release immune-stimulating agents that provide long-term immunity. For safety purposes, they also included a “kill switch” in the engineered cancer cells. An injection of rapamycin, a widely available antibiotic, or ganciclovir, an antiviral, would activate the kill switch, shutting down the cells if they “go rogue” and begin to proliferate like cancer—although Shah believes this scenario is unlikely. Finally, Shah’s team encased the engineered cells in a gel and added it to the brains of mice with glioblastoma, after their tumors were surgically removed. (This surgery-first approach is used in 85 percent of human patients with glioblastoma.) Cancer cells that linger in the brain after surgery, Shah explains, are culprits in future tumor growth. The engineered cells prevented the tumors from returning.
The researchers tested the dual-purpose cancer cells in “humanized” mice. To create an environment that mimics the human body, they implanted each mouse with immune cells from human bone marrow, liver, and thymus, a small gland in the chest that is part of the lymphatic system. Two months after the initial surgery, scientists reintroduced glioblastoma cancer intracranially in the opposite hemisphere of the mouse brains. Remarkably, no tumors appeared: the engineered cells previously implanted in the brains had trained the immune system to prevent tumors from forming.
One of Shah’s pressing priorities is to test this technology in patients. The work is still in a preclinical stage, a heartbreaking circumstance for people currently affected by glioblastoma and their loved ones, several of whom have contacted Shah to ask if his vaccine is ready for human trials. He predicts that such studies are at least three years away, but stresses that patients remain top of mind for him. In fact, his team chose to use the humanized mouse models, which add some complexity to their research, hoping to speed the path to human use in the clinic.
They also plan to develop a second-generation vaccine for use in other types of brain tumors, including advanced cancer that metastasizes from the breast and lung. Shah believes the technology could also be used to treat cancers in other parts of the body. “If we can figure out a cure for brain tumors,” he says, “we can figure out a cure for other solid tumors as well.”