Cancer-killing viruses fight high grade gliomas

The team are exploring the use of tumour-killing viruses, like one called Reovirus, that can be injected into the bloodstream and have been shown to reach the brain. Five different viruses are being investigated for their tumour-killing potential.

The team are testing these viruses in tumour cells in the lab. Their investigations are showing 1) how the virus replicates within the tumour cells, 2) the virus’s killing effects on the tumour cells and 3) whether the virus stimulates an immune response against the tumour. The most effective virus will be tested against tumours in pre-clinical models and assessed for: changes in an MRI scan; the impact on survival; immune response and how much virus reaches the tumour.

Many drugs are unable to reach a brain tumour as they cannot pass through the protective barrier that separates the brain from the bloodstream, known as the blood–brain barrier (BBB). However, blood cells are able to pass through the BBB. The team at Leeds are investigating whether immature blood cells taken from the bone marrow, called haematopoietic stem cells (HSCs), can be used as a method of delivering chemotherapy drugs to gliomas.

HSCs, that have been altered to fluoresce green, will be introduced into pre-clinical models. This means Professor Short’s team can visually track the movement of these blood cells through the body and confirm that they home in on the brain. The HSCs will then also be modified to contain and release drugs, which will prevent the tumour cells from thriving, and hopefully lead to tumour death.

As well as taking these new treatment approaches, Professor Short recognises that the quickest way to improve treatment success is to make current therapies more effective. Therefore, this third project aims to increase the effectiveness of conventional radiotherapy using two different approaches.

Wnt signalling

When tumour cells are damaged by radiotherapy, it’s thought that a process called ’Wnt signalling’ repairs the cells and aids tumour regrowth. By blocking Wnt signalling, the team are testing whether they can make radiotherapy more effective and prevent regrowth after treatment.

miRNA

Small molecules called miRNA switch genes on and off, which in turn regulates cellular processes. This regulation is essential to maintain a balanced environment within the cell, and within the body. Professor Short is particularly interested in this, as certain cell processes can increase tumour growth or cause tumour death. By identifying miRNA mimics and blockers, tumour death can be started, and tumour growth can be stopped.

Delivery of these small molecules to the brain is an ongoing challenge due to the BBB, so the team is also looking at different delivery methods to get these molecules to the brain (including the potential of using viruses for delivery).

The laboratory testing for the Reovirus has been completed and has shown promising results. Separate to this grant, Reovirus is being tested in a human clinical trial, known as REOGLIO, which we co-fund with Cancer Research UK. The tests for another virus, HSV1716, have also shown promising results, confirming that the virus successfully stimulates an immune response when delivered into the bloodstream.

The team successfully developed HSCs that release a drug to block TGF-β, a molecule known to promote tumour growth. Testing the HSCs in pre-clinical models, in conjunction with radiation, has shown promising results.

Laboratory experiments blocking Wnt signalling in human cells provided inconsistent results. Therefore, this area of the project was halted.

The team identified a miRNA mimic, but there was no effect on survival in their tests. They also saw no effect on survival when using the HSV1716 virus as a vehicle to carry the miRNA mimic to the brain.

The success of this project has led to a new, early phase clinical trial using the HSV1716 virus. We look forward to following this up in the future.

The team are now also exploring the interaction between the HSV1716 virus therapy and traditional cancer treatments (including radiation).

The team are repeating experiments using HSCs in larger experiments to confirm their results. This will provide more evidence for their hypothesis that the HSCs are good drug delivery candidates.

To see if experiments blocking Wnt signalling should continue, the team are screening human cells to eliminate any genetic differences and, hopefully, inconsistencies in results they see.

To increase the effectiveness of the miRNA mimic, the team are going to explore other methods of delivering the drug to the brain.