Case Western Reserve School of Medicine researcher part of effort to modify adenovirus to seek and destroy cancer cells
While doctors can successfully treat some types of skin cancer at the surface with human-engineered viruses, scientists have yet to find a way to inject these types of viruses to seek and destroy other cancers in the body, such as lung cancer.
But medical researchers at Case Western Reserve University and Emory University are reporting remarkable success in eliminating human cancer cells in mouse models by injecting a modified strain of adenovirus into the bloodstream.
Their findings were published in the journal Science Translational Medicine on Nov. 25.
“You have to be cautious with saying this is a ‘first,’ or the ‘first time,’ but I don’t know of any other engineered oncolytic virus that can function in the body after IV injection, find metastatic disease and, in some cases, completely clear that tumor,” said Phoebe L. Stewart, a professor of Pharmacology and member of the Cleveland Center for Membrane and Structural Biology at the Case Western Reserve School of Medicine. “While it is not yet ready for humans, this is a major step forward—and really the culmination of my entire scientific career.”
Oncolytic viruses, some found in nature and others modified in the laboratory, are a class of viruses that can infect and kill tumor cells, reproducing efficiently in the tumor without harming healthy cells.
Stewart worked for the last five years on this project with longtime collaborator Dmitry M. Shayakhmetov, professor of Medicine at Emory University School of Medicine.
How they did it
Stewart’s lab at Case Western Reserve, led by PhD student and co-first author Corey Emerson, performed cryo-electron microscopy and structural modeling to visualize the engineered adenovirus generated by their collaborators at Emory University. Each change in the engineered virus allowed it to evade a particular defense by the body.
“The goal was to design and study the structure of a modified form of a respiratory virus, adenovirus, so that it can better evade the immune system, target and kill cancer cells,” Stewart said.
The Emory team, led by Shayakhmetov and co-first author Svetlana Atasheva, tweaked the adenovirus (named the Ad5-3M virus, indicating three different engineered mutations) to successfully skirt three antiviral immune responses.
Those three responses were:
- Binding: Factors in the blood itself bind the virus and try to clear it through the liver.
- Cytokine storm: Flexible loops on the structure of the virus interact with the body’s host cells, triggering a massive and possibly deadly release of a group of proteins or peptides called cytokines.
- Pathogen clearance: Multiple components of the immune system act in a concerted way to clear pathogens from the body.
The Case Western Reserve team used cryo-electron microscopy—the technique behind the 2017 Nobel Prize in chemistry that employs supercooling of viruses, imaging with an electron microscope—and computer processing of massive data sets to show Shayakhmetov and his lab where to alter the virus and to visualize the impact of those alterations.
“We ran a series of molecular dynamic simulations and computational analyses,” said Emerson, who wrote the research as part of his doctoral thesis. “You have to have a strong understanding of the structural properties of the virus to be able to know how to alter it. We provided structural hypotheses that guided how our collaborators altered the virus. The result was everything we could have hoped for.”
For more information, contact Mike Scott at mike.scott@case.edu.
This article was originally published Nov. 30, 2020.