Brain tumours kill more children and adults under the age of 40 than any other cancer
The 22nd annual meeting of the American Society for Neuro-Oncology (SNO)
Despite the publication of a number of negative clinical trials over the previous 12 months, there was a definite sense of purpose at this year’s SNO meeting with a tangible determination to learn from the trial failures and use this information to help us to move forwards to develop better treatments and ultimately a cure.
A wide variety of topics were discussed during the meeting with multiple sessions taking place in parallel. These covered a wide range of topics from basic science through clinical trials to patient quality of life. A number of key themes emerged where there is definite evidence of the translation of basic science through into the clinical arena. Here is a flavour of a few areas that may be the most promising in the shorter term.
The first of these focused on the mechanisms by which cells become resistant to the action of anti-cancer drugs. This is of particular importance for brain tumours, considering the small number of therapies that are available to treat the condition. The main reason underlying the lack of response to therapies is the fact that tumours are not uniform, but there are many different types of cells contained within an individual tumour. This is termed heterogeneity. When a tumour is treated with a drug that may kill the majority of cells, there is likely to be a residual number that have survived because of their biochemical composition. These may remain dormant, or may start to regrow. Any subsequent tumour is therefore more likely to be more resistant to therapy because it is made up of these different types of cells. Therefore, it is vital that we understand the basis of these differences in the cells within a single tumour that make them resistant to existing therapies so that new treatments can be developed. Tumours also contain “tumour stem cells” which can transform into a number of different cell types, and this provides yet another mechanism for cells to develop resistance to drugs and also needs further investigation. The biochemistry of tumour stem cells forms the focus of our research centre at Queen Mary University of London, who presented some of their research at the meeting.
Following the negative outcome of the trial of the immunotherapy-based drug nivolumab which was reported earlier this year, there has been a renewed interest in this area of research and in particular, how we may be able to harness the body’s own immune system to treat tumours. Because the brain has a relatively weak inherent immune system, the use of a single approach is unlikely to have a major therapeutic benefit. This may explain why nivolumab, which stimulates existing immune cells within the brain, failed to be effective. So, it will be necessary to take a multi-pronged approach. Vaccines targeted against components of tumour cells are being developed which spark off an immune response in the region of the tumour. Although none of the trials reported to date have shown any positive effect, the suggestion is that they will need to be combined with other factors that stimulate additional elements of the immune reaction. Similarly, it is possible to engineer immune cells which are directed against factors specifically expressed on the surface of tumour cells. These are called CAR-T cells and are currently used for the treatment of leukaemia. While initial trials have taken place to demonstrate that this type of therapy could be feasible for the treatment of certain kinds of brain tumours, there has been some evidence of the development of CAR-T cell resistant cells within tumours. The overall consensus is that any single immune-based therapy may not be sufficient to stimulate a strong immune reaction to kill all of the tumour cells. However, if some of these could be given in combination, this could spark off a sufficiently powerful response to destroy the tumours. However, side effects associated with the development of an immune response within the brain cannot be ruled out. Therefore, discussions are now underway to determine which combinations are most likely to be of benefit while having minimal adverse effects.
In addition to the development of cell-based therapies, there were a number of presentations on other novel therapies. The insertion of external genes to modify the genetic make-up of tumour cells is an area that is rapidly developing. At least three products are now in early stage clinical development. These make use of viruses that infect dividing tumour cells, but have little effect on normal nerve cells. A number of different approaches have been taken including the expression of suicide genes in the tumour cell and the introduction of an enzyme which converts a specific chemical into a toxin. It is also considered that these genetic approaches will involve the immune response in their effect. The initial clinical studies on a small number of patients all reported that the therapies were safe and appeared to have some benefit. However, further larger scale clinical trials will be required before we know for certain that these will be effective for use in the clinic and that there will be no serious long-term side effects. It will also be important to identify those people who are most likely to respond best to the therapy.
There have been a number of individual reports that cannabis may be effective for people with certain types of brain tumour and a clinical trial has been carried out in the UK to assess the potential therapeutic effect of sativex, which is a synthetic cannabinoid currently used for the treatment of muscle spasms in people with multiple sclerosis. The results of the study were reported at the meeting and patients with recurrent GBM who were treated with sativex in combination with temozolomide responded better than those who were treated with temozolomide alone. It was recommended that a larger trial be carried out to identify those who are most likely to respond best to this therapy. Brain Tumour Research will be following this closely.
One of the more controversial therapies to be introduced in the last few years is called “tumour-treating fields (TTF)” which is marketed as Optune®. This involves the passing of very small electrical currents through the brain from electrodes which are placed on the skull and connected to an external battery pack. This must be worn for 18 hours per day in order for it to be effective. Results published at the SNO meeting last year suggested that this may increase survival rates for patients with high grade GBM. There were concerns over the results as some considered that the trial may not have been designed correctly. Another problem is the fact that TTF is classified as a medical device rather than a drug and therefore is assessed under different legislation. This means that the company doesn’t have to demonstrate how the device works, unlike with an ordinary drug. If we don’t understand how a therapy mediates its clinical effect, it is difficult to determine whether the clinical effect is real, or whether it may be due to other associated factors. So a lot of research has been carried out in the interim 12 months to really understand how TTF can influence the growth of tumour cells in order to provide evidence that the clinical effect is genuine. The numerous results presented at the meeting suggest that passing small electrical currents through cells prevents them from dividing. This would corroborate the clinical results associated with a decrease in tumour growth. However, further clinical trials are ongoing to confirm the efficacy of the product and how it could best benefit patients, were it to be made available.
Overall, there was a definite feeling of optimism at the meeting, with findings from basic science being translated into the development of potential new therapies. Most of these are at an early clinical trial stage with small numbers of patients being enrolled in single centres, primarily in the US as this is where a lot of the companies are based. However, because of the small number of effective therapies currently available for the treatment of brain tumours, some of the most promising are already being fast-tracked through the regulatory agencies to ensure that, if they are demonstrated to be safe and effective, they will be made available for use in the clinic as fast as possible.