Cancer-Killing Viruses Enter in Stealth Mode, Penetrate Immune Barrier

Viruses that, when administered to patients, preferentially attack and kill cancer cells, leaving normal tissues unscathed. It might sound like science fiction, but oncolytic viruses are, in fact, already a (small) part of oncologists’ toolkit. Five years ago, the U.S. FDA approved the first and only oncolytic virus therapy called talimogene laherparepvec (T-VEC, or Imlygic®), a course of treatment prescribed to metastatic melanoma patients with tumors that can not be accessed surgically.

If they work, why aren’t there more oncolytic virus treatments in circulation to treat other cancer types? The main problem is convincing the human immune system that these are the good guys. Once in the bloodstream, immune cells flag the viral treatment as potentially pathogenic, promptly whisking viral particles away to the liver for inactivation and excretion.

Now, cancer researchers have made a breakthrough, identifying a way to sidestep immune clearance—by re-engineering the virus such that it can enter the body in stealth mode.

“We think it will be possible to deliver our modified virus systemically at doses high enough to suppress tumor growth—without triggering life-threatening toxicities,” said the study’s lead author Dmitry Shayakhmetov. The findings were featured in Science Translational Medicine.

Oncolytic viruses have sparked safety concerns in the medical community after a series of adverse reactions that led to fatalities in their clinical trials. Some recipients experienced exaggerated inflammatory responses after receiving therapeutic doses of the viruses, which led to cytokine storms and multiple organ failures. These unfortunate events stopped more viral therapies from pushing forward, inspiring Shayakhmetov to go back to the drawing board with viral vector design. The idea: to re-tool oncolytic adenoviruses so that they can sneak past innate immune defenses.

“This is a new avenue for treatment of metastatic cancers,” explains Shayakhmetov. “You can arm it with genes and proteins that stimulate immunity to cancer, and you can assemble the capsid, a shell of the virus like you’re putting in Lego blocks.”

Shayakhmetov and colleagues from Emory University modified the adenovirus in three distinct sites, shielding viral-host interactions without compromising viral particle assembly and cancer-killing functionality. Additionally, the team swapped out a segment of the adenoviral vector that targets host integrins for one that binds to laminin-a1, a protein abundant in tumors. 

The researchers tested their new-and-improved viruses in a mouse cancer model with exciting outcomes. Here, tumors of human lung cancer cells were grafted into the mice prior to receiving oncolytic viral therapy. As predicted, the “original” unmodified adenovirus set off severe systemic inflammatory cascades, culminating in liver damage and the eventual death of these mice within days. 

High doses of Shayakhmetov’s adenovirus 2.0, however, had the opposite effect—the mice survived, and even better, 35 percent of the mice showed completely undetectable levels of tumors after treatment. In these animals, where cancer cells once thrived, there was only scar tissue. 

According to Shayakhmetov, testing this treatment in human patients with metastatic lung cancer would be the stepping stone towards eventual clinical adoption.

Sources: Science Translational Medicine, Emory University.