Tumour-targeting viruses hold hope for incurable brain cancers

Using bacteria-killing viruses to deliver cancer therapies could help to tackle deadly brain cancers, according to new early-stage research.

The approach is being explored by researchers to treat glioblastoma, an aggressive, incurable form of brain cancer which kills many patients within the first year following diagnosis.

Glioblastoma can spread rapidly through the brain, requiring surgery or radiotherapy to remove the tumour and treat affected parts of the brain. Currently, the only available chemotherapy is a drug called temozolomide (TMZ). However, it has limited effect.

Now, an international team led by researchers at Imperial College London has had promising results using specialised viruses called bacteriophages or ‘phages’ to target cancer cells in the brains of mice.

These tumours can grow very fast and can be resistant to the existing treatments we have Dr Amin Hajitou Division of Brain Sciences

Using the approach, they were able to deliver targeted therapy directly to cancer and amplify the effect with TMZ. The treatments led to tumours shrinking while leaving healthy tissues intact as well as increasing the life expectancy of the animals.

According to the team, the approach has the potential to improve outcomes for patients affected by glioblastoma though they stress that human trials are now needed to back up the findings seen in animal studies. They suggest trials in cancer patients could begin within the next 3-5 years in the USA or in the UK.

“Glioblastoma is a devastating form of cancer” said Dr Amin Hajitou, from the Division of Brain Sciences within Imperial’s Department of Medicine, who led the research. “These tumours can grow very fast and can be resistant to the existing treatments we have, so there’s a real need to develop new, effective therapies for patients.”

Dr Hajitou added: “Our latest work shows that in mice with glioblastoma, combining this viral therapy with low dose temozolomide leads to regression of tumours and the best survival benefit. We have generated cancer-targeting viruses that do not enter healthy cells and are therefore safe for use in human tissues.” 

Specialised viruses

At the heart of the approach are bacteriophages, or ‘phages’ – specialised types of virus that are perfectly evolved to target bacteria. These viruses, which resemble a kind of alien lunar lander, latch onto the surface of a bacterium and insert their genetic material into the cell, ultimately destroying the bacterium.

Despite the threat to bacteria, phages are unable to infect animal cells and so are harmless to humans. This trait has led to them being used previously to target bacterial infections such as meningitis, as well as being explored as a viable alternative to antibiotics.

In the latest study, published recently in the journal EMBO Molecular Medicine, Dr Hajitou’s team looked to harness the specificity of the tiny bacteria-killers and put them to work fighting cancer cells instead of bacteria.

They used a genetically modified virus called an M13 phage to target tumours and deliver a killer payload to the cancer cells.

The phages were modified to target receptors found exclusively on the surface of cancer cells. But the team also edited the virus’s genetic material to include a therapeutic gene. When the viruses come into contact with a cancer cell and insert their genetic material, the therapeutic gene is activated and produces a protein that destroys the cell.

We observed huge improvements and, in some cases, full regression of tumours and complete response to treatment Dr Amin Hajitou Division of Brain Sciences

To test the approach, glioblastomas were taken from adults and children who had died from the cancer and transplanted into mice.

Once the phages were injected into the animal, they accumulated in the tumours in the mouse’s brain, leaving the healthy tissues untouched.

Giving the animals doses of TMZ then amplified the process, boosting the effects of the gene therapy delivered by the phages and helping to reduce the size of the tumours.

Less than one month after treatment, those mice receiving the phage-targeted therapy plus TMZ showed not only a lack of tumour growth but a substantial reduction in the size of the tumours – in both adult and child glioblastomas.

What’s more, they found that phage therapy plus TMZ showed the greatest survival benefit compared to TMZ or phage therapy alone – on average, mice receiving phage-TMZ therapy outlived the either treatment alone, and control animals, in some cases surviving more than 84 days after tumour implantation.

Multiple cell targets

At the cellular level the virus was able to target and destroy three types of cells within glioblastomas. Along with the cancer cells themselves, the virus killed cells of the new blood vessels feeding the tumour.

But crucially, the phages also targeted and killed cancer stem cells – undifferentiated cells that can become cancer. It’s these cells which may be most resistant to treatment and which can enable cancers to regain a foothold if any of the cells are missed during surgical removal of tumours.

While the team are necessarily cautious about the findings, they are hopeful that the mounting safety evidence for phage therapy along with a drug already available to patients could speed up the development of this combination therapy for what is currently an incurable form of cancer. 

“We have already performed safety studies of the virus in larger animals, in pet dogs with natural tumours and which would have otherwise died from their cancers without treatment,” said Dr Hajitou.

“In these studies we observed huge improvements and, in some cases, full regression of tumours and complete response to treatment. Taken together, we are confident these studies prove that our virus is safe.”

Following the initial success of the approach, a US company is now developing a form of the virus to take forward to clinical trials. But the Imperial researchers are confident they can improve on the existing work, creating more efficient cancer-killing phages.

“Over the course of this research we have generated more powerful viruses that can be up to 100 times more effective than the phages used in our experiments,” explains Dr Hajitou. “We will now test them in treating brain cancers from children and adults. The hope is that we will be able to take these forward to clinical trials in the UK and Europe.”

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‘Efficacy of systematic temozolomide-activated phage-targeted gene therapy in human glioblastoma’ by Justyna M. Przystal et al. is published in EMBO Molecular Medicine. DOI: 10.15252/emmm.201708492