The next generation of cancer therapies?

The US Food and Drugs Administration (FDA) have recently announced the approval of a new product for the treatment of leukaemia. This therapy is ground-breaking because it was the first time a patient’s own immune cells have been engineered to recognise tumour cells as being harmful in order to eliminate them. This is an exciting advance in the area of cancer therapy development, but what does it mean for the future treatment of brain tumours?

In a large number of cancers, including brain tumours, the body’s immune system is essentially tricked into believing that the cancer cells are normal and therefore the immune response remains dormant and does not destroy them. This allows the cells to continue to divide and multiply and for the tumours to grow. Immunotherapies, which can be used to treat certain cancers, work to re-activate the immune system so that the cancer cells are recognised as being “foreign“ and are ultimately destroyed by the immune cells. This approach is being used to treat many different types of cancer, although the results of initial immunotherapy trials for the treatment of brain tumours published earlier in the year were disappointing.

Another approach is to modify the genes within the body’s blood-based immune cells so that they can target specific components on the surface of the tumour cell in order to destroy it. These are called CAR T cells. The immune cells are removed from a patient’s blood and grown in the lab where specific genes are inserted into them. This changes their ability to identify what are “foreign” cells within the body. The engineered cells are then re-injected into the patient’s bloodstream where they immediately target blood cancer cells that are present in leukaemia. Other early stage clinical trials are currently underway to determine whether this approach could be used for other types of cancer.

While there are no specific CAR T-based therapies currently in clinical trials for the treatment of brain tumours, a number of other novel therapies are under development, although these are all still at an early stage. DCVax-L uses brain tumour tissue removed following surgery to prime a patient’s own immune cells and therefore make them more efficient at identifying and destroying the tumour. The blood cells are removed from the patient, exposed to factors derived from the tumour to activate them, and then re-injected into the patient. It is hoped that these will then ultimately target and kill the tumour cells.

Another approach is to use viruses to change the genetic make-up of the tumour cells. DNX-2401 is a virus which specifically binds to glioblastoma cells and then injects in a gene which causes the cells to commit suicide. Another way in which viruses can be used is to insert genes into the cells which will make them more susceptible to the actions of specific drugs.One of these is Toca 511 which injects the gene specifically into tumour cells to make them much more susceptible to the drug which can be given at a relatively low dose that does not harm other cells in the brain.

In addition to making new viruses, a recent report has suggested that existing ones, such as the Zika virus, could also be used to treat brain tumours as it preferentially targets cells in the brain which are growing rapidly, such as tumour cells, while having little effect on normal brain cells. Some of the key research in this area is being carried out by Harry Bulstrode at the University of Cambridge who was named the Brain Tumour Research/BNOS young researcher of the year in June this year for his work in the area.

All of these therapies are classified as an Advanced Therapy Medicinal Products (ATMPs) which are regulated by the Committee for Advanced Therapies at the European Medicines Agency, of which I am a member. There is a large number of these therapies in early stage clinical trials to treat many different diseases, including brain tumours. It is a rapidly evolving field with new advances being made almost on a daily basis and I think that it shows great promise for the future. But, we also need to consider that these cutting-edge therapies are not without their risks. Indeed, some of the early studies on leukaemia-associated CAR T therapies had significant adverse effects with one trial having to be halted at an early stage. As with all new therapies, it is key to demonstrate that they are safe as well as being effective. This is one reason why clinical trials can take a relatively long time, especially when testing state-of-the-art technologies such as this.

Through its centres of research excellence, Brain Tumour Research is forging ahead to further understand the changes that occur when nerve cells transform into tumour cells, as this is information is key for the development of new ATMPs. We also constantly monitor all developments in the area of new therapy development and we will ensue that our supporters will be kept up to date with all of these advances

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Why is there such a high failure rate for brain tumour clinical trials and how can we improve this?

A paper published recently in the journal Neuro-Oncology  reported that although new drugs may appear to have a clinical benefit in early phase clinical trials for the treatment of glioblastoma, this is frequently not observed in the subsequent later stage trials. So why does this happen, and how can we increase the accuracy of the initial trials?

Clinical trials are initiated following evidence from laboratory studies that a drug may have a clinical benefit. There are three categories:

  • Phase I usually involves a small number of patients and is focused on assessing the safety of the drug and identifying the approximate dose which will be used in subsequent trials. It may monitor whether the drug has a positive clinical effect, but this is not the primary reason for the trial;
  • Phase II trials enrol a larger number of patients and they involve an assessment of the efficacy of the drug. The trial may be carried out in a single location or in a small number of centres depending on the capacity for patient recruitment. This may contain a control (placebo) group, but this will be dependent on the disease and the treatment being tested. The results from this trial will usually determine whether further trials should take place;
  • Phase III trials usually take place across a number of different locations and involve a larger number of patients. The aim is to confirm the results from the smaller phase II trial and also to identify potential side effects of the drug so that these can be considered when the drug is ultimately made available in the clinic.

This research assessed 11 phase III clinical trials which were carried out since 1992, seven for newly diagnosed glioblastoma and four for recurrent disease. While all had positive phase II trial results, only one reported a successful outcome in phase III. The study asked why this anomaly occurred and how can it help in the development of future drug trials.

The first problem to be addressed is the trial design. Quite frequently, the phase II trials didn’t include a control group of patients actually taking part in the trial (referred to as an active control group) but rather used clinical data from patients who had taken part in previous studies (historical data). However, the value of this data depends on the patients from whom it was collected and what other therapies they may have been on. The inclusion of an active control ensures that their clinical information is being collected by the same doctors at the same time. They are also being treated with an existing therapy, such as temozolomie, and this can then be compared with the new drug to see which is the most effective. While the inclusion of an active control group makes the trial more expensive, it would ensure that any positive results were associated with the new therapy rather than differences observed due to the use of historical data.

The second challenge is to define what is meant by a “positive trial outcome” – how do we define success? This can be determined by a number of criteria. One outcome measure is called “overall survival” (OS) which refers to the time between the initial treatment and death, but assessing this means that the trial may have to be carried out over a long time. Another is “progression-free survival” (PFS) which is the time between the treatment and the recurrence of symptoms. PFS is usually assessed when determining the shorter term benefits of a drug. However, other indications of drug response, such as imaging, should also be considered as this will provide an on-going indicator of progression of the tumour size and potential development. And chemical tests, called biomarkers, are being developed which will allow for a rapid assessment of how well the tumour is responding to the therapy.

Clinical trials also need to take into account the genetic differences between patients. The WHO guidelines published last year classified subgroups of patients who may have the same brain tumour type according to its pathological make-up, but yet have different genetic profiles. Therefore, recruitment into early-stage clinical trials should take these differences into consideration so that the participants are as similar as possible. The lack of genetic data is another reason why the use of historical control data may not be appropriate.

A new strategy to test multiple treatments and combinations of treatments in parallel is being developed to make clinical trials more efficient and informative.  These are referred to as “adaptive trials” and are designed to be continuously updated to incorporate the latest information about brain tumours. This means that ineffective treatments can be shut down early, and new treatments can be initiated quickly. Two trials are currently being designed using this approach including INSIGhT and GBM-AGILE. This trial protocol has previously been used to test drugs for other types of cancer.

There are only a small number of trials currently underway for new therapies to treat brain tumours. However, this report has emphasised that it is important to design new trials appropriately to maximise the possibility of a successful outcome.

 

Further details of current brain tumour clinical trials in the UK can be found at http://www.brainstrust.org.uk/brain-tumour-hub/clinical-trials.php.

Other useful websites include:

www.ukctg.nihr.ac.uk – UK clinical trials register

www.clinicaltrials.gov – a searchable list of all US clinical trials, including some taking place in Europe

www.clinicaltrialsregister.eu/ctr-search/search – European clinical trials register

 

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World Federation of Euro-Oncology Societies – Day 3

The third day of the WFNOS conference started on rather a low note. There were three review presentations, each of which reported on recent clinical trials which had failed. In some cases, this followed a promising start in a small number of patients, but the results could not be reproduced in larger trials. The trial data is currently being reanalysed to determine whether subgroups of patients may have had a positive response, so there is still the potential that some of these drugs may eventually enter the market. In addition to clinical trial data, there are also a number of existing clinical databases which can be analysed in order to be able to identify who will react best to a specific therapy. Using detailed genetic, clinical and pathological data on thousands of patients obtained from a large national cancer database, a research group in France analysed 3,000 cases of type III glioma. Detailed mathematical analysis allowed the researchers to predict the prognosis in up to 82% of patients. Studies such as this will be vital in the identification of the best therapies for individual patients.

Of particular disappointment were the results from immunotherapy trials as these had appeared to hold great promise. Dr David Reardon from Boston went through each of them in detail to try to understand why this therapeutic approach had failed. The general conclusion is that brain tumours are unique so they are less likely to respond to the immune system in the same way as tumours in other parts of the body. So we need to try to understand the reasons behind these differences and use this information to design future trials. These may include the combination of a number of the drugs used previously, or the development of new drugs.

But, new drugs are extremely expensive to develop and wth such a high failure rate, not all drug companies are willing to invest in new drugs to treat brain tumours. Another approach is drug repurposing as some drugs which are already on the market may act on brain tumours. Our researchers at the University of Portsmouth have already demonstrated that aspirin can kill glioma cells. So work is now being carried out on “repurposing” this drug by designing a clinical trial which may start later this year. This is an exciting area of research and one in which the UK leads the field.

Overall, while the meeting was interesting, research into the treatment of brain tumours is still at a relatively early stage when compared with other cancers and I think that we particularly need to focus on the identification of viable targets for new drugs. Drugs which target known mutations, particularly in GBM, have shown little or no clinical benefit. This highlights the importance of the research being carried out at the Brain Tumour Research-funded Centres of Excellence. By combining basic molecular and cellular approaches, we are more likely to identify new and more viable drug targets.

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World Federation of Neuro-Oncology Societies – Day 2

There were two key themes at the second day of the WFNOS conference. In addition to the development of new and more effective therapies, we also need to identify people who are most likely to benefit from them. This is due to the significant differences between brain tumour types and also between the individual cells that are present within a single tumour.

 

We know that there are a number of key genes associated with the development of brain tumours, and these have been incorporated into the WHO classification guidelines which were published last year. One of these, IDH1, is important in controlling cell division and it is mutated in certain brain tumours. A study showed that inhibition of the gene may have therapeutic potential by stopping the growth of a tumour. But this therapy would only be only be suitable for patients with a specific mutation in the IDH1 gene. Following surgery, a genetic profile of the tumour is carried out and this genetic information will be vital when developing therapies which are targeted to individual genes.

 

The potential for the development of an IDH1-related vaccine for the treatment of brain tumours was also discussed by a number of researchers. This approach has been tried for the mutant form of IDH1 which is expressed in some tumour cells. Small portions of the IDH1 protein were injected into the blood and these generated antibodies against the protein, which only bind to tumour cells. Initial studies reported that this stops the tumour from growing but does not actually kill the cells. At the same time, a number of immunotherapy trials have been carried out to assess the benefit of the drug nivolumab. This acts by stimulating the immune cells which are close to the tumour so that they can identify the cells as being “foreign” and therefore destroy them. The results of the nivolumab trial were disappointing with no evidence that it may be of benefit for people with brain tumours. However, there are now plans to combine the two therapies. So, the vaccine will generate the antibodies to attack the tumour cells and the immunotherapy will stimulate the immune system to remove the weakened tumour cells.

 

Similar joined up approaches were also proposed for the development of other new therapies. It can be disheartening to hear about all of the clinical trials which have had negative results but researchers are now considering how we could possibly combine the appropriate new therapies to act together rather than assessing each drug individually. No single drug is likely to be completely effective in the treatment of brain tumours but a rational approach to the combination of therapies could provide an exciting way forwards.

 

Surgery to remove a tumour is the first line of treatment for a majority of patients. The Brain Tumour Research Centre at Imperial College has been developing the iKnife tool which can remove the maximum amount of the tumour with minimal damage to surrounding brain tissue. A new approach to increase the efficiency and specificity of tumour tissue was presented. Metal particles are coated with a substance which allows them to enter into tumour cells, but not normal cells. Then using an apparatus similar to a microwave, the metal is heated and this makes the cells very fragile. They are then more likely to respond to subsequent radio- and chemotherapy. While this approach is novel and could have therapeutic potential, the initial trial has been halted because of potential side effects and patient drop-out. As the electrical waves are targeted at metal, the patients were required to have all metal tooth fillings to be extracted prior to therapy. The system is now being refined so that the electrical microwaves can be localised and a new study is planned To start next year. As with the Optune system described yesterday, we need to think “outside the box” when considering new therapies for brain tumours.

 

So, when today’s sessions finished, it was obvious that the research community is now reaching the stage where they realise that the traditional approach may not be effective for the treatment of brain tumours and that the best way forward will be to consider the development of new but exciting new therapeutic approaches.

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World Federation of Neuro-Oncology Societies – day 1

The 2017 World Federation of Neuro-Oncology Societies (WFNOS) conference started today with a discussion on the identification and potential therapeutic exploitation of changes that occur in tumour cells. Alterations in the expression of key genes in the tumour cells and cause them to stop functioning normally and to multiply to form tumours which increase in size. One of the components which controls the expression of key genes is called the “TERT promoter” which has the ability to turn genes on and off. In a large number of brain tumour cells, there is a mutation in this piece of DNA which means that the cell loses its ability to determine which which genes should be turned on and off. Experiments have been carried out using the drug eribulin which is currently used for the treatment of breast cancer. Initial studies have shown that it can cross into the brain and stop the growth of brain tumours. These exciting results are now being used to design a clinical trial which may start in Japan later this year.

However, when planning a trial, it is important to be able to identify which patients are likely to respond to specific drugs. We know that bevacisumab (Avastin) was effective for patients although the majority showed no response. Clinical data from a number of studies around the world has been assessed to determine whether we can identify factors which will allow us to predict patients who are more likely to respond to specific drug therapies. This information can then be coupled with the new diagnostic guidelines published by the WHO last year and this will be vital for the future design of clinical trials.

Although we immediately think of drugs when new therapies are announced, a novel approach has been under trial for the last few years. “Optune” consists of a series of small metal electrodes attached to the scalp and held in position by a skin-tight cap, similar to a swimming cap. This is attached to a portable battery which passes currents through the electrodes into the brain. The therapy, termed tumour treating fields (TTF), makes use of the fact that all cells in our body contain both positively and negatively charged elements. Passing a small electric current through them can influence how they work. The current modifies the 3-dimensional structure of brain tumour cells and prevents them from dividing and tumour growth. Initial results reported last year suggested that this treatment can increase survival for people with brain tumours. The results announced today have followed participants in the clinical trial for up to five years and have reported a survival rate of 13% for those treated within Optune in combination with temozolomide (TMZ) compared with 5% for TMZ alone. The average overall survival time from diagnosis was 16 months for TMZ and 20.9 months for Optune and TMZ.

These results are very encouraging and demonstrate that there are other therapeutic approaches that could be developed which fall outside of the definition of a traditional “pill”. The studies carried out so far have been carried out on a subgroup of people with newly diagnosed glioblastoma and further studies are required to really understand who will benefit most from this therapy. One of the obstacles will be cost – there is an estimate of £24,000 per month to rent the equipment in the UK for each patient. In order to make it available for those who will benefit from it, discussions will need to take place with the NICE in the UK to determine whether the therapy will be made available routinely on the NHS.

While the primary focus of the meeting has been on brain tumours, there is a lot of research being carried out on secondary – or metastatic – brain tumours which have arisen from tumours elsewhere in the body. These are termed metastatic tumours. They are most likely to have developed from breast, lung or skin tumours with up to 40% of cells from these tumours spreading to the brain. Because they aren’t derived from brain cells, they cannot be treated in the same way that we would usually treat primary brain tumours. There was a discussion on how best to diagnose and then treat these tumours, considering that they have originated from another part of the body.

But studies suggest that a small number of drugs directed against tumours in other parts of the body may actually cross the blood barrier to kill these metastatic cells which have entered the brain. The next question is whether these drugs may also kill tumour cells which originate within the brain. Some studies are underway to answer these questions and we will keep you updated on any progress which may lead to the development of new therapeutic strategies for the treatment of brain tumours.

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Can cannabis help brain tumours?

The potential therapeutic use of cannabis and its constituents for the treatment of brain tumours is gaining great popularity. This has included reports of the use of cannabis oil, which is available via the internet, in addition to some people sourcing the cannabis plant illegally within the UK. However, within the US, twenty-six states and the District of Columbia currently have laws broadly legalizing marijuana in some form and has limited availability in some European countries, although it is under strict control.

 

Are there any cannabis-based drugs available?

There is one cannabis-based drug is, Sativex, which is manufactured by GW Pharmaceuticals. The drug is licensed for prescription for the alleviation of spasticity in people with multiple sclerosis and is administered as an oral spray. The main active ingredients of the cannabis plant are called cannabinoids. There are a number of these compounds, and the two that are contained in Sativex are Δ(9)-tetrahydrocannabinol (THC), which is the addictive component of cannabis, in combination with cannabidiol (CBD). Sativex was rigorously tested for its safety and efficacy before receiving approval, and is distinguished from cannabis in its raw form by its specific components. The composition, formulation and dose have been developed to provide medicinal benefits with minimal psychoactive effects.

 

Is there any evidence for the clinical benefit of cannabis?

Some preclinical studies have been carried out in mouse models and while the results look promising, it is necessary to determine whether they can be replicated in humans. They suggested that although the drug does not appear to have a direct effect on brain tumours, it may make them more sensitive to radiotherapy. Clinical studies have recently been carried out to assess the potential benefit of Sativex when given in combination with temozolomide. Although the interim results of the trial appear to be promising, we need to wait for the complete data which should be available in the summer before any specific conclusions can be drawn. At the moment, it is permissible for a doctor to prescribe the drug “off-licence” i.e. for the treatment of a condition for which it has not been approved. This would be at the discretion of the clinician who must carefully consider the evidence that is available for the clinical benefit of the drug in addition to any potential adverse effects of the drug. Furthermore, the patient may have to pay for the cost of the medication and it is unlikely that the cost would be reimbursed by private health insurance as it is being prescribed off-license. Considering these limitations and the lack of any evidence of clinical benefit, we are not currently aware of any cases where it has been prescribed.

 

Are there any benefits from taking cannabis oil?

Some people have used cannabis oil as a potential treatment for their brain tumour and it contains the non-addictive CBD component of cannabis. This is marketed as a health rather than a medicinal product which means that different regulations apply. The manufacturers are not permitted to make any claims about the efficacy of the agent for the treatment of specific medical conditions. Furthermore, although the product is manufactured in accordance with general manufacturing guidelines to ensure that it is safe, there is no independent quality testing to confirm the amount of compound present in the product, despite what may be stated on the label. This unreliability makes it difficult to assess whether there are any health benefits. However, once claims are made about the benefit of the cannabis oil (or other healthcare products) for specific medical conditions, it now comes under medicinal (rather than health) product guidelines and therefore has to undergo clinical trials in the same way as any other medicine before it can be made available. This is likely to be by prescription rather than as an “over the counter” product. Furthermore, the quality testing would be much more rigorous in order to confirm the exact components present in the oil.

 

So, what are the next steps?

We are eagerly awaiting the full results of the two clinical trials which have been carried out. If they appear to show a benefit of the drug, a further larger trial will probably be required to confirm the effect. The trial would also determine whether the drug is acting directly on the tumour to modify its growth or is making it more sensitive to existing therapies. This would then provide the evidence for the licensing of the drug to treat certain types of brain tumours. It may be possible to allow limited use in the clinic when the larger trial is taking place, but this would be at the discretion of the regulatory authorities and is likely to be very controlled for a restricted group of patients who are most likely to benefit. In the meanwhile, Brain Tumour Research will keep a close eye on all developments in the area and keep people informed of all developments.

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Drug repurposing – the development of potential new therapies

Following trials to assess their safety and efficacy, drugs are usually approved for use in the clinic by the regulatory authorities for the treatment of a specific disease. This is referred to as the drug “license” – the condition for which it can be prescribed. However, an increasing number of studies have shown that drugs which have been approved for one condition may be effective in the treatment of others. This is referred to as drug repurposing. The advantage of this approach is that the drugs will have passed the initial safety stage of drug development so that they can immediately go into clinical trials.

 

How can we identify these drugs?

A drug acts by influencing certain chemical reactions, or pathways, within a cell. This usually influences how the cell works. In the brain, for example, it may cause nerve cells to produce chemicals that are associated with the transmission of electrical activities between cells. However, in certain circumstances, modification of these pathways may damage or even kill cells. This is what we want to harness in order to destroy the cells within brain tumours. In addition to drugs that are in use for other conditions, there may be others which had been tested in trials for another condition, but failed to show any significant clinical benefit for that specific illness. It is worthwhile testing some of these based on our knowledge of how they work. Brain tumour cells grown in a dish in the laboratory can be used to carry out initial tests to determine whether the drug will kill the cells. We can also grow normal nerve cells in the lab. This is important because we want the drug to target tumour cells without harming the other brain cells.

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Are there other factors that we should consider?

One of the challenges associated with treating brain tumours is the ability of the drug to get into the brain. The blood brain barrier – which is a membrane that surrounds the brain – prevents many drugs from entering the brain. But Prof Geoff Pilkington at the Brain Tumour Research centre at the University of Portsmouth has developed a model of the barrier. So as well as being able to test whether the drugs may be effective to treat tumours, we can also assess their potential ability to enter into the brain.

 

Is there any evidence of this for the treatment of brain tumours?

Research funded by Brain Tumour Research has demonstrated that a specific formulation of aspirin may enter into the brain and could be effective for the treatment of glioblastoma . This research is still at an early stage, and will need further studies before clinical trials can begin. However, the results to date are promising. Our research centre at Portsmouth have also demonstrated that an anti-depressant drug, clomipramine, may also be able to kill tumours. However, this drug may have harmful side effects so the researchers are trying to understand the mechanisms by which it may kill cells and whether there may be other drugs which can have the same effect on the cells without the side effects. Studies have also been carried out on the anti-epileptic drug sodium valproate with mixed results. While there is no indication that people who take the drug over a long period of time have a lower  incidence of brain tumours, there is some evidence that it may act to increase the efficacy of temozolomide, which is the primary drug use to treat brain tumours.

 

So, what is the next stage?

The UK Department of Health is leading a new initiative to develop guidelines for the repurposing of drugs. This is a key component of Brain Tumour Research’s manifesto and we will be working very closely with this group to develop guidelines to get potential repurposed drugs into clinical trials as quickly as possible. We will also be highlighting this as a priority for the research centres

 

 

 

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