Several cancer researchers have already created “smart bombs” that allow the orderly release of two different anti-cancer drugs.
But scientists say the missing is the “stealth bomber” – a delivery system that can slip through the body’s radar defenses. And now they believe the newly modified virus could eliminate tumor growth in patients with metastatic cancer.
“This is a new way to treat metastatic cancers. It can be armed with genes and proteins that stimulate immunity against cancer, and the virus coat can be assembled, as if you were putting in lego cubes,” said lead author Professor Dmitry Shaykhmetov of Emory University School of Medicine in the United States.
The importance of cancer-killing viruses, known as tumorigenic viruses, has been discussed and tested for decades.
One of these viruses was approved by the Food and Drug Administration (FDA) in 2015 against skin cancer.
The body’s defense system quickly picks up the viruses injected into the bloodstream and sends them to the liver, the body’s waste disposal system.
Now, researchers have found a way to re-engineer the virus delivery system so that the virus is not easily picked up by parts of the immune system. This makes it possible to inject the virus into the blood without causing a severe inflammatory reaction.
Professor Shaikhmetov said, “The innate immune system is very effective in sending viruses to the liver when they are given intravenously. For this reason, most tumor viruses are transferred directly to the tumor, without affecting the metastases. In contrast, we believe it will be possible to systematically deliver our modified virus.” In doses high enough to suppress tumor growth – without causing life-threatening systemic toxicity. ”
The study includes a structure for the re-engineered conduction system, and the ability of the virus to eliminate tumors spread in mice.
The scientists focused on re-engineering adenovirus, a delivery system used in dozens of cancer clinical trials, to stimulate the host’s anti-tumor response.
Adenoviruses have also been central to gene therapy studies.
Shaikhmetov recalls the death of Jesse Gelsinger during a 1999 clinical trial of a gene therapy.
The volunteer died of a cytokine storm and multi-organ failure associated with high doses of an adenovirus carrier delivered into the bloodstream.
“This event inspired me to re-equip the adenovirus, so that it does not cause a strong inflammatory reaction,” Shaikhmetov said. It views the reengineered adenovirus as a platform technology, which can be adapted and customized for many types of cancer, and even to individual cancer patients as a form of cancer treatment.
Shaykhmetov began working on the modified virus technology while at the University of Washington and founded a company, AdCure Bio, to provide a treatment that could potentially save lives for patients suffering from common diseases.
And in 2012, he published research on how adenovirus interacts with a single host factor in the blood, clotting factor X, in Science.
Professor Phoebe Stewart, co-author of the study, of Case Western Reserve University in Cleveland, Ohio said, “Sometimes, even small changes in structural proteins can be catastrophic and prevent the infectious virus from pooling. In this case, we modified the adenoviruses in three places. To reduce the virus’s interactions with specific blood factors, we found that the virus is still aggregating and remains effective for infecting and killing cancer cells.
It is still possible for a slower adaptive immune response to the modified virus, similar to what was observed in the vaccine.
The researchers say a combination of viruses could be used among cancer patients, to expand the therapeutic benefits.
“Our study is the first to show that we can modify IgM’s natural association with the adenovirus. We have introduced mutations that prevent inactivation of the virus in the bloodstream and trap it in hepatic macrophages, which is the largest concentration of immune cells in our bodies that trap and destroy pathogens,” Shaykhmetov said. “Is that any regular repetitive structure, such as the virus envelope, would attract a low binding to the natural IgM antibodies, leading to their immediate inactivation and removal from the blood.”
The researchers also replaced a portion of the adenovirus that interacts with human cellular integrins (membrane proteins embedded in the plasma membrane of living cells), and replaced a sequence of another human protein that targets cancer cells with the virus.
When injected into mice, the high doses of the standard adenovirus caused liver damage and death within a few days, but the modified virus did not.
The modified virus can eliminate tumors spread from some but not all mice implanted with human lung cancer cells.
A complete response was observed in about thirty-five percent of the animals. The scientists found that tumor sites in the lung turned into scar tissue.
Now, Professor Shaikhmetov’s lab is exploring ways to increase the overall response rate.
The results are published in the journal Science Translational Medicine.