Immunotherapy for Brain Tumours

Scientists are working hard to understand why some patients respond better than others, so that immunotherapy can become more effective for greater numbers of patients. They are also exploring whether it might be more effective to combine it with other treatments such as chemotherapy and radiotherapy.

Results from large randomised clinical trials are still needed before any firm conclusions can be drawn regarding immunotherapy’s ability to cure brain tumours.

There are various forms of cancer vaccines which are given to a patient to encourage an anti-tumour immune response. These include peptides which mimic tumour antigens, whole lysed tumour cells, RNA and DNA vaccines. The one that has been developed furthest in clinical trials for brain tumours is a dendritic cell vaccine.

This innovative treatment takes immune cells called dendritic cells from a patient, and ‘re-programmes’ them to stimulate an immune attack on a range of targets on cancer cells, as well as recruiting other immune cells to help, thereby involving the whole immune system.

Oncolytic viruses are viruses that can infect and kill cancer cells. They are injected directly into tumours during neurosurgery, where they are then able to replicate themselves in high enough numbers to attack and kill the tumour cells. It is now known that a key element of this approach is to allow the immune system to see and kill tumour cells. They are therefore sometimes referred to as ‘in situ’ vaccines.

This involves harvesting patients’ T cells from a blood sample, and engineering them in a laboratory so that they can recognise and target a specific protein on the cancer cells. This is done by creating unique receptors on the T cell surface called chimeric antigen receptors or CARs, which when they identify their target on tumour cells will switch on the ability of the T cell to kill the tumour cell.

Personalised, engineered CAR-T cells are then grown in a lab until hundreds of millions of cells are created. Once returned to a patient’s bloodstream, these empowered cells can identify and attack the cancer cells they’ve been targeted towards.

The aim is for the CAR-T cells to stay in your body for long periods of time, continuing to multiply whilst attacking your specific cancer cells.

CAR-T cells have led to remarkable responses in some types of leukaemia (cancer of the blood).

Why are brain tumours difficult to treat with CAR-T cell immunotherapy?

In solid tumours such as brain cancer the cells are packed together, making it more difficult for the CAR-T cells to reach the receptors on each cell. In comparison, leukaemia cells are spread throughout the blood stream and the receptors are easier to connect with.

One form of CAR-T cell immunotherapy in clinical trials for recurrent glioblastoma multiforme (GBM) brain tumours is focused on a protein called EGFRvIII (epidermal growth factor receptor variant III), a mutated protein that is only made in brain tumour cells. However, proteins such as EGFRvIII are only made on a subset of brain tumour cells rather than all of them.

In addition, all immunotherapies have to overcome the brain tumour microenvironment (the environment immediately surrounding the tumour) which is highly immunosuppressive, and has evolved to resist killing by immune cells. Researchers are investigating further forms of engineered CAR-T cells or seeking to identify combination therapies that may be able to overcome such challenges

What are immune checkpoints?

Immune checkpoints are immunosuppressive proteins that program immune cells to shut down, instead of enabling them to recognise cancer cells as a threat and attack them. This is an important mechanism that brain tumours and other cancers use to trick the immune system, hence allowing the tumour to grow. The discovery of how to inhibit immune checkpoints (prevent them from working) has led to major breakthroughs in some forms of cancer, and was recently recognised with the 2018 Nobel Prize for Physiology and Medicine. 

What are immune checkpoint inhibitors?

Immune checkpoint inhibitors are drugs that target these very specific immune checkpoint proteins, so that the tumour can no longer give this false signal that cancer cells are safe to ignore. Instead, T-cells are alerted to the presence of the tumour and the immune system begins to attack the cancer cells. This approach is called immune checkpoint blockade.

Which immune checkpoint inhibitors work for brain tumours?

Some of the checkpoint inhibitors currently under investigation for use in brain tumours include

• Ipilimumab 
  
• Pembrolizumab 
  
• Nivolumab 
  
• Pidilizumab

Checkpoint inhibitor drugs whose name end in –mab are also known as monoclonal antibodies.

MABs consist of copies of a particular antibody that is designed to target a specific protein found on cancer cells. For example, bevacizumab (trade name Avastin) is a monoclonal antibody drug designed to target a protein that stimulates the growth of new blood vessels (angiogenesis). Monoclonal antibodies that target immune checkpoints are classified as immune checkpoint inhibitors.

Monoclonal antibodies are used to treat many diseases, including some types of cancer. To make a monoclonal antibody, researchers first have to identify the right antigen to attack. 

Much of the research in brain tumours is focused on antigens that mark cells involved in particular signalling pathways: named because these are pathways of molecules that work together to give certain signals to cancer cells that enable them to grow. These pathways are promoting cancer rather than healthy cell function because an aspect of their molecular structure is changed (mutated) at some point in their development, so if a monoclonal antibody can block a mutated molecule’s function, it can stop it from continuing along its destructive path.

There are now multiple clinical trials exploring these combinations and as scientists learn more about how these approaches work in patients, we could expect that personalised tailored immunotherapy combinations will emerge as promising approaches for brain tumour treatment. 

However, it is important to keep in mind patient safety as a strong immune response in the brain may lead to side effects caused by inflammation and swelling in particular. Indeed, several immune therapies have shown side effects on patients due to an over-activated immune system and so this remains a challenge that needs to be overcome before immunotherapy for brain tumours can move safely out of the clinical trials environment and into standard treatment regimes.