Immunotherapy and gene therapy double attack against glioblastoma shows therapeutic potential

A combinatorial approach using immunotherapy and gene therapy has been explored by researchers at the University of Michigan against the highly aggressive brain tumour, glioblastoma (GBM).

“We hope the implementation of our gene therapy strategy for gliomas, used in combination with immune checkpoint blockade, will eventually provide successful treatment for patients with this devastating brain cancer”, says Maria Castro Ph.D., Professor of Neurosurgery and Cell and Developmental Biology at University of Michigan.

Immunotherapy uses the body's natural defence system (immune system) to recognise and destroy tumour cells. Previous research has allowed us to understand that GBM tumours are very resistant to immunotherapy because of their excellent ability to communicate with other cells nearby in a co-ordinated way to block this action. This creates a type of environment by GBM tumours, known as an immunosuppressive microenvironment.

“For the first time, we proved that a type of immunosuppressive cell within the tumour environment play a major role in determining the impact of immunotherapies”, Castro says.

The team report that the accumulation of immunosuppressive cells, called myeloid-derived suppressor cells (MDSCs), are powerful inhibitors of anti-tumour immune responses.

The study results displayed great evidence that reducing the levels of these cells in the tumour microenvironment increased the effectiveness of immunotherapies.

The team also explored ways in which they could overcome the immunosuppressive microenvironment to increase the number of immune cells recruited to the tumour site. They did this by combining immunotherapy with gene therapy on tumour cells in the laboratory.

This entailed injecting the tumour cells with a type of virus, called an adenovirus, which had been modified to carry an enzyme that cause tumour cells to break down and a protein that recruits immune cells called dendritic cells.

By breaking the tumour cells apart, proteins that are specific to the tumour cells called antigens are released. Dendritic cells then pick up the tumour antigen from the tumour site and process it to initiate an immune response towards the tumour.

Researchers used this gene therapy combined with a type of immunotherapy called immune checkpoint blockade to stop the cancer cells from hijacking the immune system.

“We report much higher therapeutic efficacy in preclinical brain tumour models using the combination of both therapies, leading to an increase in median survival”, says Dr Pedro Lowenstein, University of Michigan. “This effect is not seen with either approach on its own”.

So, how could this research transform future treatments for glioblastoma patients?

The results of this study provide very early pre-clinical evidence supporting the development of combination immune-stimulatory strategies aimed at overcoming GBM-induced immune suppressed and the use of immunotherapy in GBM.

The gene therapy is currently being tested in a phase one clinical trial at the University of Michigan and researchers hope that translating this combinatorial approach from bench to bedside should be possible in the near future.

Read more about Dr Maria Castro's research