A ‘stealth bomber’ virus could be the new killer weapon against cancer – and it’s put together like Lego blocks.
Many cancer researchers have already devised “smart bombs” that allows a controlled release of two different anti-cancer drugs.
But scientists say that what has been missing is the stealth bomber – a delivery system that can slip through the body’s radar defences.
Now they believe that the newly engineered virus could stamp out tumour growth in metastatic cancer patients.
Study lead author Professor Dmitry Shayakhmetov, of Emory University School of Medicine in the US, said: “This is a new avenue for treatment of metastatic cancers.
“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.”
Cancer killing viruses, known as oncolytic viruses, have been discussed and tested for decades.
One such virus against melanoma was approved by the Food and Drugs Agency (FDA) in 2015.
But scientists have always faced an overwhelming barrier in the fight against metastatic cancers, being the human immune system.
The body’s defence system quickly quickly captures viruses injected into the blood stream and sends them to the liver, the body’s rubbish disposal.
Now, researchers have found a way around that barrier by reengineering the virus delivery system so that the virus is not easily caught by parts of the immune system.
This makes it possible to inject the virus into the blood without causing a massive inflammatory reaction.
Prof Shayakhmetov said: “The innate immune system is quite efficient at sending viruses to the liver when they are delivered intravenously.
“For this reason, most oncolytic viruses are delivered directly into the tumour, without affecting metastases.
“In contrast, we think it will be possible to deliver our modified virus systemically at doses high enough to suppress tumour growth — without triggering life-threatening systemic toxicities.”
The study includes a structure of the re-engineered delivery system and the virus’s ability to eliminate disseminated tumours in mice.
Scientists focused on reengineering adenovirus, a delivery system that has been used in dozens of cancer clinical trials to stimulate host anti-tumour response.
Adenoviruses have also been central to gene therapy studies.
Prof Shayakhmetov recalls the death of Jesse Gelsinger during a gene therapy clinical trial in 1999.
The volunteer died of cytokine storm and multi-organ failure connected with high doses of an adenovirus vector delivered into the bloodstream.
Prof Shayakhmetov said: “That event inspired me to retool adenovirus, so that it would not set off a strong inflammatory reaction.”
He views the re-engineered adenovirus as a platform technology, which can be adapted and customised for many types of cancer, and even to individual cancer patients as a form of personalised cancer therapy.
Prof Shayakhmetov started working on the modified virus technology while he was at the University of Washington and founded a company, AdCure Bio, to bring a potentially life-saving therapy to patients with metastatic disease.
In 2012, he published research on how adenovirus interacts with one host factor in the blood, coagulation factor X, in Science.
Co-study author Professor Phoebe Stewart, of Case Western Reserve University in Cleveland, Ohio, said: “Sometimes even small changes in structural proteins can be catastrophic and prevent assembly of the infectious virus.
“In this case, we modified adenovirus in three places to minimise virus interactions with specific blood factors.
“We found that the virus still assembles and remains functional for infecting and killing tumour cells.”
It is still possible for a slower-building adaptive immune response to develop to the modified virus, similar to that observed with a vaccine.
The researchers say a panel of viruses could be used among cancer patients to extend therapeutic benefits.
Prof Shayakhmetov said: “Our study is the first to show that we can modify the binding of natural IgM to adenovirus.
“We introduced mutations that prevent virus inactivation in the bloodstream and its trapping in liver macrophages, the largest pool of immune cells in our body that trap and destroy pathogens.
“Up to now, the prevailing view has been that any regular repeating structure, like the shell of the virus, would attract low-affinity natural IgM antibody binding, leading to its prompt inactivation and removal from the blood.”
The researchers also replaced part of the adenovirus that interacts with human cellular integrins, substituting a sequence from another human protein that targets the virus to tumour cells.
When injected into mice, high doses of standard adenovirus triggered liver damage and death within a few days, but the modified virus did not.
The modified virus could eliminate disseminated tumours from some, but not all mice engrafted with human lung cancer cells.
A complete response – lack of detectable tumours and prolongation of survival – was observed in about thirty five percent of animals.
And scientists found tumour sites in the lung were converted into scar tissue.
Now, Prof Shayakhmetov’s lab is exploring approaches to further increase the proportion of complete responders.
He added: “In the clinic, metastatic lung cancer would be the type of cancer most appropriate to test an oncolytic virus against.
“The technology could also be harnessed for gene therapy applications.”
The findings were published in the journal Science Translational Medicine.