Engineered 'stealth bomber' virus could benew weapon against metastatic cancer25 November 2020

Engineered adenovirus Ad5-3M with highlighted in redmutations that were introduced to target virus to tumorcells, reduce inflammation, and avoid interactions withblood factors and immune cells after systemicadministration. Credit: Dmitry Shayakhmetov

Many cancer researchers can claim to havedevised "smart bombs." What has been missing isthe stealth bomber—a delivery system that can slipthrough the body's radar defenses.

Oncolytic viruses, or viruses that preferentially killcancer cells, have been discussed and tested fordecades. An oncolytic virus against melanoma wasapproved by the FDA in 2015. But againstmetastatic cancers, they've always faced anoverwhelming barrier: the human immune system,which quickly captures viruses injected into theblood and sends them to the liver, the body'sgarbage disposal.

Researchers at Emory and Case Western Reservehave now circumvented that barrier. They've re-engineered human adenovirus, so that the virus isnot easily caught by parts of the innate immune

system. This makes it possible to inject the virusinto the blood, without arousing a massiveinflammatory reaction.

A cryo-electron microscopy structure of the re-engineered virus and the virus's ability to eliminatedisseminated tumors in mice are reported in Science Translational Medicine.

"The innate immune system is quite efficient atsending viruses to the liver when they are deliveredintravenously," says lead author DmitryShayakhmetov, Ph.D. "For this reason, most oncolytic viruses are delivered directly into thetumor, without affecting metastases. In contrast, wethink it will be possible to deliver our modified virussystemically at doses high enough to suppresstumor growth—without triggering life-threateningsystemic toxicities."

The co-first authors of the Science TranslationalMedicine paper are Emory associate scientistSvetlana Atasheva, Ph.D. and Case WesternReserve graduate student Corey Emerson.Shayakhmetov is professor of medicine andpediatrics at Emory University School of Medicineand a member of Lowance Center for HumanImmunology and Emory Vaccine Center.

Shayakhmetov has been working for 15 years withstructural biologist Phoebe Stewart, Ph.D.,professor in the Department of Pharmacology anda member of Cleveland Center for Membrane andStructural Biology at Case Western ReserveUniversity. Their focus: re-engineering adenovirus,a delivery system that has been used in dozens ofcancer clinical trials to stimulate host anti-tumorresponse.

Adenoviruses have also been central to genetherapy studies. Shayakhmetov recalls the 1999death of Jesse Gelsinger, a volunteer in a genetherapy clinical trial who died of cytokine storm andmulti-organ failure connected with high doses of an

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adenovirus vector delivered into the bloodstream.He says that event inspired him to retooladenovirus, so that it would not set off a stronginflammatory reaction. He views the re-engineeredadenovirus as a platform technology, which can beadapted and customized for many types of cancer,and even to individual cancer patients as a form ofpersonalized cancer therapy.

"This is a new avenue for treatment of metastaticcancers," Shayakhmetov says. "You can arm it withgenes and proteins that stimulate immunity tocancer, and you can assemble the capsid, a shellof the virus, like you're putting in Lego blocks."

A high-resolution microscopic image showing the fullcapsid structure of Ad5-3M, the modified oncolytic virusdesign. Credit: S. Atasheva et al., Science TranslationalMedicine (2020)

Shayakhmetov started working on the modifiedvirus technology while he was at the University ofWashington and founded a company, AdCure Bio,to bring a potentially life-saving therapy to patientswith metastatic disease.

In 2012, Shayakhmetov's and Stewart's labspublished a cryo-EM analysis of how adenovirus

interacts with one host factor in the blood,coagulation factor X, in Science.

"Sometimes even small changes in structuralproteins can be catastrophic and prevent assemblyof the infectious virus," Stewart says. "In this case,we modified adenovirus in three places to minimizevirus interactions with specific blood factors. Wefound that the virus still assembles and remainsfunctional for infecting and killing tumor cells."

It is still possible for a slower-building adaptiveimmune response to develop to the modified virus,similar to that observed with a vaccine. A panel ofviruses could be used for sequential administrationto cancer patients to extend therapeutic benefits,Shayakhmetov says.

The spread of the engineered adenovirus (green) throughnodules of human lung adenocarcinoma leads to death ofcancer cells (red). Credit: Svetlana Atasheva and DmitryShayakhmetov; Lowance Center for Human Immunology,Department of Pediatrics, Emory University School ofMedicine

"Our study is the first to show that we can modifythe binding of natural IgM to adenovirus. Weintroduced mutations that prevent virus inactivationin the bloodstream and its trapping in livermacrophages, the largest pool of immune cells inour body that trap and destroy pathogens," he says."Up to now, the prevailing view has been that anyregular repeating structure, like the shell of the

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virus, would attract low-affinity natural IgM antibodybinding, leading to its prompt inactivation andremoval from the blood."

The researchers also replaced part of theadenovirus that interacts with human cellularintegrins, substituting a sequence from anotherhuman protein, laminin-?1 that targets the virus totumor cells. Emerson and Stewart obtained a highresolution cryo-electron microscopy structure of there-engineered virus (see figures).

When injected into mice, high doses of standardadenovirus triggered liver damage and death withina few days, but the modified virus did not. Themodified virus could eliminate disseminated tumorsfrom some, but not all mice engrafted with humanlung cancer cells; a complete response—lack ofdetectable tumors and prolongation of survival—wasobserved in about thirty five percent of animals.Tumor sites in the lung were converted into scartissue, the scientists found. Now, Shayakhmetov'slab is exploring approaches to further increase theproportion of complete responders.

In the clinic, metastatic lung cancer would be thetype of cancer most appropriate to test an oncolytic virus against, Shayakhmetov says. The technologycould also be harnessed for gene therapyapplications.

More information: S. Atasheva el al., "Systemiccancer therapy with engineered adenovirus thatevades innate immunity," Science TranslationalMedicine (2020). stm.sciencemag.org/lookup/doi/ …scitranslmed.abc6659

Provided by Emory UniversityAPA citation: Engineered 'stealth bomber' virus could be new weapon against metastatic cancer (2020,November 25) retrieved 22 November 2021 from https://medicalxpress.com/news/2020-11-stealth-bomber-virus-weapon-metastatic.html

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