The medical playbook against tumors is typically a three-pronged approach: cut as much of the tumor out as possible, then attack it with radiation and chemotherapy drugs. But some tumors don’t make it easy. Brain tumors, for example, are difficult to extract without causing serious and permanent damage to surrounding healthy tissue. Whole brain radiation produces side effects, and only beats back the cancer for so long. Drugs have trouble reaching the brain due to the blood-brain barrier, a protective layer that keeps most molecules out. Current chemotherapy regimens are also dose-restricted, due to the devastating side effects related to toxicity to normal tissues throughout the body – significantly affecting quality of life.
To get around these obstacles, researchers have proposed a new strategy using genetically modified viruses to target and kill tumor cells. But the first trials of this “oncolytic virotherapy” fell short, because the injected viruses either failed to reach their tumor cell prey or were themselves eradicated by the immune system before they could execute their orders. Now, stealing a move from the playbook of the ancient Greeks, scientists at the University of Chicago Medicine and City of Hope have found a novel way to sneak their viral weapon to the tumor’s front door, where they can launch their attack.
The secret, found Maciej Lesniak and Karen Aboody, is loading the viruses like cargo into an unusual package: neural stem cells. Neural stem cells have the natural ability to seek out and target invasive brain tumor cells — leaving normal tissues alone.
“We’re using them as a vehicle,” said Lesniak, professor of surgery and neurology at the University of Chicago Medicine. “You load the virus into this car and let it go. Not only do they disperse through the tumor mass and migrate selectively to invasive tumor cells, they also lessen any immune rejection, because they hide or protect the virus from the immune system until it gets to the target. “
As a disease target, the researchers chose glioblastoma multiforme, a particularly invasive and lethal brain tumor where there are currently few options for patients.
“Because patients die within a year or two of diagnosis and current therapies have such undesirable side effects, there is a desperate need to develop novel therapies” Lesniak said. “There’s nothing else really that works. In the last 100 years, there have only been three new therapies approved — none of which are curative.”
The basis of this therapy are the customized viruses that Lesniak’s lab constructed from an adenovirus, a common virus responsible for many upper respiratory infections. But two key genetic modifications transform the virus from a cause of illness to a tumor killer. First, the viruses are attracted to a receptor called pk7 that is expressed in higher numbers by brain tumor cells relative to normal brain cells. Second, because viruses work by entering a cell and hijacking its DNA to replicate itself, Lesniak’s group modified that process so that only a type of promoter found in tumor cells but not normal cells can trigger this viral reproduction.
But while these changes make sure viruses select the right targets, getting them selectively to the tumor targets is another matter. Because humans are often exposed to adenoviruses at some point in their lives, the immune system tends to recognize the modified virus as an enemy and attack them before they reach the tumor cells. Even if they evade these immune defenses, early preclinical trials found that the viruses struggle to travel too far away from where they are injected in the brain — a particular problem for glioblastoma multiforme, where the tumors can be large and widely dispersed.
“Wherever you injected these cells making the virus, they stayed close to the injection site,” said Aboody, associate professor of neurosciences and neurosurgery at City of Hope in California. “The problem wasn’t the virotherapy concept, the problem was ineffective delivery to the tumor sites.”
After a chance encounter at a scientific meeting, where they were both awarded an outstanding new investigator award, and presented their work back to back, Lesniak and Aboody realized that they were separately working on two halves of a novel solution to this problem. Aboody’s laboratory was testing the use of neural stem cells as a delivery vehicle for a different type of cancer therapy, where the stem cells secrete an enzyme to activate a precursor to an active chemotherapeutic agent. These stem cells — isolated years ago from a fetal source and then immortalized and cloned to produce limitless supplies — are attracted to sites of brain injury, for reasons that scientists don’t yet fully understand. Working together, the two laboratories tested whether loading these neural stem cells with the modified adenovirus would be a successful pairing to combat gliomas induced in animal models.
To their delight, the combination worked — and even made both components even more effective at their jobs. Viral infection enhanced the migration of the stem cells away from the injection site to their tumor targets, and as they traveled, the passenger viruses replicated and prepared to strike.
“They’re like little factories where these vectors replicate and make a more robust agent of choice to kill these tumors,” Lesniak said.
By labeling the stem cells with iron particles, the researchers plan to visualize the path they travel after injection into the brain by magnetic resonance imaging (MRI). In animals with implanted tumors, imaging revealed a parade of virus-loaded stem cells leading from the injection site to the tumor. Most importantly, the therapeutic impact was highly significant, as animals injected with the virus-loaded stem cell Trojan horses lived almost twice as long as control animals, or those injected with virus alone.
These promising results in conjunction with FDA approval for human use of these neural stem cell vehicles, have put this novel therapy on track for clinical trials in humans. Currently, Aboody’s group is running a phase I safety trial in recurrent glioma patients, using an enzyme/prodrug localized chemotherapy approach. Lesniak said the researchers hope to test the stem cell-virotherapy within the next two years, and predicts that, if successful, the strategy could have implications beyond the field of brain tumors.
“I think this approach may change many gene therapy applications, not just for cancer,” Lesniak said. “It overcomes two of the biggest challenges that the field has encountered. We’re doing something to change the field of gene therapy, which I think is very important.”
Atique U. Ahmed, Matthew A. Tyler, Bart Thaci, Nikita G. Alexiades, Yu Han, Ilya V. Ulasov, and Maciej S. Lesniak (2011). A Comparative Study of Neural and Mesenchymal Stem Cell-Based Carriers for Oncolytic Adenovirus in a Model of Malignant Glioma Molecular Pharmaceutics DOI: 10.1021/mp200161f