In a recent publication in Nature a vaccine was created against a mutated IDH1 gene that prevented growth of brain tumours in mice, with human trials next in the pipeline. But what does this actually mean?
First, this mutation is found in about 70% of gliomas, a brain tumour that appear to be made up of glial cells (the support cells of the brain), these tend to be quite slow growing, however Glioblastoma Multiforme (GBM) is one of the most aggressive and deadly forms of cancer possible. Around 5000 people die from brain tumours in the UK every year, with a much greater proportion of children developing brain tumours than other forms of cancer.
What is IDH1?
The IDH1 gene is involved in metabolism, and plays a role in the production of a chemical called 2-oxyglutarate (2OG), which is essential for the function of other proteins that regulate a process called DNA methylation, which helps to control the expression of many different genes. When IDH1 is mutated (almost always in the exact same way, which makes creating a vaccine much easier and more effective) it changes it's function, producing 2-hydroxyglutarate (2HG) rather than 2OG. This interferes with DNA methylation related functions, in this case it results in a lack of expression of tumour suppressor genes and therefore genes that lead to cancer (oncogenes) are no longer suppressed. This is what is known as a driver mutation, as this mutation is one that contributes towards the progression of the cancer, there are also normally dozens if not hundreds of passenger mutations in other genes, but they do not have any effect on the progression of the tumour.
How Does The Vaccine Work?
Tumours do normally cause an immune response, however it is normally not strong enough to overcome the disease and eliminate the cancer. The vaccine contains a shortened form of the peptide that contains the mutation, which is thought to enable the immune system to better recognise cancer cells that carry the mutation, and therefore help the body to fight the disease by itself without harming any healthy cells. This particular gene mutation is particularly promising when compared to others, as it is so common in gliomas and is an early mutation and therefore most (if not all) of the tumour cells contain the mutation, meaning the development of this vaccine would be worthwhile.
So What Did They Find?
This proof of principle study vaccinated mice with a human form of the major histocompatibility complex (MHC), which is necessary for an immune response, against the IDH1 mutation. This makes the model a more accurate representation of the possible response in humans. The mouse response was an activation of a specific type of immune cell called the CD4 positive T cell, which was able to regulate and control IDH1 mutation containing tumours in the body. In this case they were sarcomas rather than gliomas, although the principle remains the same. The researchers also found that 4/25 patients with gliomas had an innate immune response to the tumour, that was initiated by the same type of T cell. The next step will be to test the vaccine in human trials.
This type of vaccination could also be used in conjunction with other immunotherapies that target the microenvironment of tumours, thus making it harder for them to survive, without affecting healthy tissue. These new immunotherapies are very promising and could be effective therapies in humans in years to come. They are much preferable to currently used chemotherapy and radiotherapy which does much damage to healthy cells aswell as cancer cells.
T. Schumacher et al., “A vaccine targeting mutant IDH1 induces anti-tumour immunity,” Nature,doi:10.1038/nature13387, 2014.