The Coming Treatments for Brain Tumours

 

Radiotherapy has come a long way in terms of being more precise and more accurately delivered says Dr Mike Brada, Reader and Consultant in Clinical Oncology at the Royal Marsden. Conventional radiotherapy is given with a machine called the linear accelerator (Linac) and this has become more reliable and precise.  What has really changed is the way we can image tumours so that we can see much more precisely where to go not only before treatment, but, using scanners, actually during delivery. We also have better ways of conforming treatment to protect surrounding tissue. All these are small steps which have led to a very high-tech, modern radiotherapy thats able to treat just what you see and with very little radiation to the outside. There is not zero collateral damage, but there is an improvement in every way. Thats the technical advance.

 

The machinery of delivery is much-discussed, but for Mike Brada, the main advance of radiotherapy has really been with imaging: Both CT and MRI have become much more accessible, of much better quality and much faster. We can see a lot more than we did before so its easier to treat what we see and the quality assurance procedures where you check what youre doing are much improved. Were imaging close to the treatment. The other major advance has been the recognition in malignant tumours that the combination of radiotherapy with drugs and new targeted agents may improve the effectiveness of radiation. And these are agents that target particular defects in cells and the paradigm of it is something called GF Receptor Growth Factor Receptor, which can be targeted with lots of drugs. One thats been tested is Cetuximab, an antibody thats been shown to improve results in head and neck cancer together with radiation. There are other situations where what you call ordinary chemotherapy given at the same time as radiation shows improved results.

 

 

On the scene, too, are new machines with fancy names but, Dr Brada stresses, these are mostly derivations of the original principle. The Tomotherapy machine gives radiotherapy in a slightly different way, but you can actually deliver the same treatment with the linear accelerator too. The latest in radiotherapy is something called particle (also known as proton) therapy, which is another, new form of ionizing radiation. When radiation travels it deposits energy and therefore causes damage all the way along its path. Particle therapy travels a certain distance, then stops and tends to deliver the radiation in a more localised way, so there is very little damage beyond the target point. Proton therapy has been round for 10/15 years but has been extraordinarily costly and so its been accessible to very few patients. Now the machines have become smaller and easily accessible. So they are being introduced around the world as a potentially more localised treatment. But to my mind theres a problem: it is still significantly more expensive and the actual benefit, even in physics term, compared to the best conventional treatment, is very small and the existing clinical data has not really shown any benefit. Technically it should be a little better, but it has been hi-jacked by people who have vested interest. There is industry behind it, and there are certainly some advantages theoretically its just that none of have been shown yet.  The government has approved the building of two centres in the UK but its going to be private investment a bit like pfi (private finance initiative) and that carries its own problems. It means that the priority will not be best treatment but paying the mortgage. Its big application at this moment is in radiotherapy to children which is technologically more demanding. But the jury is still out as to whether the technological disadvantages will be outweighed by the small difference in the localised deposition of the treatment. There is considerable debate about it. Its being particularly marketed for the treatment of children but whether its any better or not nobody knows. Conventional treatment with the Linac and all its add-ons is now so sophisticated that it is very difficult to make it better.

 

 

Proton therapy via a focused, specifically targeted beam, is heralded as being particularly beneficial for tumours in very closed areas where there is very complicated anatomy like the head and neck and spinal cord. However the first generation of proton beam therapy machines weighed in at 150-200m dollars and required a significant number of operators. So capital and running costs have been very high and therefore very limiting. Now the technology is much improved and simplified machines now cost more like one tenth of that figure. English patients have thus far had to be referred abroad: This year the NHS will send 60 patients to be treated elsewhere, costing 40,000 a time.  theres a major proton therapy unit in Heidelberg, and two leading centres in the States at the MD Anderson Hospital, Houston and the Loma Linda Center, Washington DC. Leading manufacturers are Protom International (their proton beam has the advantage of a targeted scanning nozzle) and the Still River System.

 

Proton therapy is said to halve the incidence of secondary tumours and to be a major development for children as delivering safe radiotherapy to small, still-growing brains requires the utmost precision.  So far, in the UK, only Clatterbridge Hospital on the Wirral offers proton therapy, but so far only for eye cancer. The NHS has shortlisted three more sites to build Britains first proton therapy centres, and a company called Care Capital is also developing a designated centre in Central London, likely to open in late 2012, early 2013. Most patients are expected to be NHS referrals.

 

 

Carbon Ions, which Dr Brada finds slightly more interesting than proton therapy. Carbon Ions is another treatment this time involving heavy charged particles, heavier than protons. There may be some biological difference in how it causes damage (to the cancer cells), but its potentially more interesting in the long-term, but at the moment it is extremely expensive and there are only two centres in the world in Japan and Germany (Heidelberg).

 

 

Medicine is moving in the direction of personalised therapy. The old view of chemotherapy was that you could individually determine the dose of a drug by the person and factors such as their weight or biochemistry. Now you can give agents such as Biologic drugs, to which the tumour is likely to respond.

 

But not every body will respond to these genetic drugs. Two types of tests, using bio-markers - are being developed. There are those that are prognostic, and can tell you if a tumour is going to respond. Unfortunately if the person tests negative for the bio-marker, they may actually do worse if the drug is used. Other tests can be predictive showing that those who are positive will have benefit, whilst also telling you what will happen if the person is negative no result/no difference or worse state.

 

A typical example of a predictive biomarker is Herceptin for breast cancer, where if you have a specific mutation the drug will work and scientists know the benefits, and not to waste it on those who are HER-2 negative. In the brain there are potential bio-markers but none of them is yet proven. Brain tumours are always a bit behind in research because there is such a small population to study. But the paradigm of breast cancer is potentially applicable to brain cancer: That a tumour will have a DNA sequence containing mutations and that developing a drug to target those specific mutations will work.

 

Unfortunately to develop the understanding and the drugs could take one or two decades.

 

At the moment, unfortunately with Temozolomide, the bio-marker is purely prognostic, not predictive.

 

Dr Brada also identifies a new approach towards personalised radiotherapy:  The example is lung cancer where we know that tumours move and tumours shrink. And the personalisation is that you dont just fix the treatment dose at the beginning. You give the treatment to a maximum dose that the patient can tolerate, depending on how much lung you are treating. And if the tumour shrinks more you can give less dose because there is less lung treated. On theoretical grounds certainly - though not yet shown clinically -  you can end up with marked improvement. Trials are just starting to show this. In the brain it is not clear that personalised radiotherapy will make an enormous amount of difference, because the tumours dont change that much. But there are some very good brain tumours- some of the benign tumours, where even a bit of radiation is extremely effective and you dont really need to improve radiation that much because side effects are very few. There are also those bad, malignant  tumours where radiation works, but not well enough, and just technical improvements are not likely to solve the problem. For these targeted therapy together with radiation is more likely to help. I do treat malignant brain tumours and we were involved in the early days of Temozolomide which has come of age and is now a routine part of treatment in malignant glioma that is obviously a success. Not everybody is cured but things are certainly better than before Id say by 10 per cent or so. In terms of benign tumours, result have been good and with modern techniques were treating less normal brain but we have to wait another 20 to 30 years before progress is demonstrated with confidence. I started here 21 years ago, and now we are getting very mature results with very few side effects.

 

 

One of the most interesting areas of development is that of Photodynamic therapy (PDT). The basics of this 100 year old quest have been to take a chemical agent which releases oxygen when light is shone on it. Oxygen kills cancer cells. Historically, the limitations have been that PDT could only be used on or just below the surface of the skin, but laser and even ultrasound energy forms have changed all that making attacks on cancer cells beyond the skull or in deep tissues more and more possible. Then there have been significant developments with the agents. Historically these have tended to be chemical in effect, drugs. Their ability to lock on to only cancer cells and leave healthy cells unharmed was imperfect. Now new agents, particularly those using algae or chlorophyll-rich natural compounds, have shown real potential. The Dove Clinic and Dr Julian Kenyon are working hard in this area.

PDT is now moving firmly into the mainstream of cancer treatment and the UK cancer Czar, Prof Mike Richards has commissioned a Department of Health report  (due to be published soon) which is expected to recommend that funding for PDT be made more available. Interesting areas of research for its application include prostate, pancreas and brain.

Much of the work that has brought it orthodox repute and approval hails from Mr. Colin Hopper, consultant head and neck surgeon, at University College London Hospital. Dr Hopper explains how contemporary PDT dates back to the early l990s when tumours were first illuminated by some fairly crude drugs. Or a century further back, if you like, to Oscar Raabs experiments on paramecia (primitive protozoa) using an acridine dye. This dye, Raab noticed. killed all the bugs when the sun was shining but not when it didnt.  He worked with his supervisor von Tappeiner to determine that this important concept was oxygen-dependent a photochemical reaction killing the cell. In l905 these two scientists cured a lip cancer, but the treatment was prolonged and unwieldy using a whole chamber of huge arc lights and large, quite unreliable lasers. In the l990s, similarly unwieldy lights were still being used, while the illuminating agent of that decade was Photofrin a chemical extract from blood.
 

One new PTD drug, developed by Ray Bonnett from the university side of the Royal London Hospital is Foscan - basically a very powerful chlorine - that is used with a small diode laser to treat tumours. Says Dr Hopper You can now get a diode laser to produce any wave length of light. The idea is that the activation wave length is matched to the absorption spectrum of the drug in question. We quickly found that Foscan, will kill tumours down a depth of about one cm. Its selective where you shine the light, but it isnt selective insofar as with the current drug you can kill cancer and leave the surrounding tissue from which it has arisen intact. What makes PDT so attractive is that it is the capacity of surrounding tissue to heal from this treatment: It differs from radiotherapy in that there are no lasting effects. Its repeatable and theres no lifelong damage to the small blood vessels that in radiotherapy become slightly ischaemic (losing blood supply).
 

In glioblastoma multiforme the most lethal of brain tumours - some of the drugs used in PDT also glow when you shine blue light at them Dr Hopper explains. And theres one drug Gliolan (or ALA) which, when injected, causes the solid bits of tumour to glow pink, when you shine light of a certain frequency on the brain during surgery. This means that you can remove much more of the tumour than is obvious to the naked eye. The problem with these particularly aggressive brain tumours is that although they appear localised, tumour can penetrate the other side of the brain and often has done by the time of presentation. What we do is to make a hole in the skull and put some fibres in so were not just treating as in the early days with surface illumination. We can now get a laser fibre into the deeper tissues so that we deliver light to a target deep within whether that is brain, head or neck, gall bladder, pancreas or other sites. The principle is the same.
 

So this treatment has not yet provided any gold-standard answer but it is a start.   Dr Hopper describes two really exciting options that are coming along: One has been used in humans but not in the brain and the other has not yet been used in humans at all. The first one is an interaction between a small amount of PDT with chemotherapy. Some chemo agents dont work because the cancer cells wrap them up in little envelopes and excrete them before they even have a chance. So the idea is to burst the little packets by using PDT photo-chemical internalisation (PTI). 14 patients have been treated, not in the brain, but lower down in the head, on a phase 1 clinical trial. With this, we do have proof of concept in head and neck but it may be applicable to brain tumours too.  But the really exciting possibility is currently being researched by Jane Ng in the Firefly Project. Fireflies make light via an enzyme called luciferase.  In the chemical reaction as it breaks the chemical luciferin in half, light is emitted. If you can get luciferase into cancer cells and that process is where the challenge has been, the cells cleave the luciferin, generate light and kill themselves. This is for the future, possibly four or five years away its currently going on in cell culture and is going into animal work. And theres more promising news from Steve Bown, retired director of the Laser Centre. Hes been doing some work to show that normal nerves dont respond to PDT. They are protected whereas cancer nerves are not. So there is some evidence that while killing a brain tumour, you are not going to do too much damage to the brain. We know that this works with peripheral nerves, from the head and neck treatments Ive carried out: we have seen no significant damage to the hypoglottal nerves or the facial nerves. The natural history of glioblastoma is bad in that it spreads outside the tumour site throughout the brain, but there are lots of theoretical reasons why the future should look good.
 

a) Tarceva (erlotinib) was first trialled on US glioblastoma patients in 2004. Known as an EGFR, it blocks epidermal growth factor which is critical to cell grown in many cancers. Manufacturers say that, unusually for a brain tumour drug,  it is very targeted, with no secondary effect on surrounding cells and bone marrow.   Researchers from the Cleveland Clinic Brain Tumor Institute have reported that Tarceva produced responses in more than 40% of patients with glioblastoma multiforme. The great hope for Tarceva is that, as a small molecule,  it may effectively penetrate the blood-brain barrier, though results were not dramatic.  Of 30 patients in the Cleveland Clinic study more than 10 per cent were progression free after  a year of treatment.

b) Cotara, a drug developed for glioblastoma multiforme patients by Peregrine Pharmaceuticals is expected to deliver full trial results by mid 2011. Cotara is a genetically engineered antibody designed to target certain cancer cells that also carries a cell-killing radioactive isotope. It is infused directly into the tumor, with the aim of sparing healthy tissue from the radiation. Initial findings from patients enrolled at a medical center in New Delhi, India are encouraging: the first 14 patients lived a median of 86 weeks, compared with expected survival of about 24 weeks for patients whose cancer has recurred. A couple of patients from an earlier trial are still alive nine year on.

 

c) Immunotherapy at Cedars Sinai Eradicating brain cancer cells by harnessing the patient’s immune system has, in theory, been an attractive treatment approach for aggressive gliomas. Certainly Dendritic cell Vaccines, are increasingly being used with cancers. An effective anti-tumor immune response initially depends on dendritic cells that constantly sample the environment and can recognize unusual proteins, such as those belonging to cancers or infectious pathogens. However, since there are few dendritic cells in the brain, the immune responses in this organ are dampened when compared to those elicited in other parts of the body. Now researchers at Cedars-Sinai Medical Center have discovered that a protein HMGB1 released from dying tumor cells - activates dendritic cells and stimulates a strong and effective anti-tumor immune response. HMGB1 does so by binding to an inflammatory receptor called toll-like receptor 2, or TLR2, found on the surface of dendritic cells. "Toll receptors play a major role in the immune system’s recognition of bacterial and viral components, but now we have shown that they also trigger an immune response against tumors," said Maria G. Castro, Ph.D., co-director of Cedars-Sinai’s Board of Governors Gene Therapeutics Research Institute and one of the article’s senior authors. "Activation of Toll receptors was essential for two key stages in initiating immune responses against the tumor the migration of peripheral dendritic cells into the brain tumor and the subsequent activation of dendritic cells and stimulation of a specific anti-tumor cytotoxic T-cell mediated response."

 

Building on more than 10 years of research in this area, the researchers used a combined gene therapeutic approach, using one protein (Flt3L) to draw dendritic cells from bone marrow into the brain tumors, and a second protein (Herpes Symplex type I Thymidine Kinase, or TK), combined with the antiviral gancyclovir to kill tumor cells and elicit long-term survival. They uncovered a novel mechanism by which tumor cell death in response to the treatment leads to the release of an endogenous tumor protein, HMGB1, which is essential to trigger the anti-tumor immunological cascade. The study showed for the first time that HMGB1 released from dying brain cancer cells activates TLR2 signaling on tumor infiltrating dendritic cells, resulting in the activation and expansion of tumor-antigen specific T cells. This caused the regression of the brain tumors and increased survival time by six months in experimental brain tumor models  Responses have also been extended to enhancing immune responses against a number of other metastatic brain cancers, such as melanoma."

 

In March this year, the US Bethesda company Northwest Biotherapeutics (NWBT) announced long-term follow up data following early clinical trials on newly diagnosed Glioblastoma multiforme patients treated with their personalised immune therapy DCVax. 33% of Patients Reached 4-Year Survival and 27% Have Reached or Exceeded 6-Year Survival. DCVax is non-toxic, unlike chemotherapies, and involves just a simple injection under the skin, like a flu shot."DCVax-Brain is a groundbreaking personalized vaccine designed to stimulate a patient’s own immune system to fight cancer.  DCVax-Brain is made up of the patient’s own "dendritic cells," the master cells which direct the immune system, that have been activated and "educated" to mobilize the whole immune system to recognize and destroy cancer cells bearing the biomarkers of the patient’s own tumour.  Each patient undergoes surgical removal of their tumor as part of the current standard of care, and also undergoes a blood draw to obtain their immune cells.

The bio-markers from the patient’s tumour tissue are exposed to the patient’s immune cells, along with certain other proprietary steps, in order to activate and "educate" the patient’s dendritic cells.  These activated and "educated" dendritic cells are injected back into the patient, in a simple small injection under the skin in the upper arm, similar to a flu shot or insulin shot.  These cell treatments are administered at a series of time points several weeks apart and then months apart.  The dendritic cells are then able to mobilise the immune system to recognize and attack the cancer, and do so without toxicities of the kind associated with chemotherapies.

 

 

Another cytotoxic therapy is the treatment of disease by either replacing damaged or abnormal genes with normal ones, or by providing new genetic instructions which may cause a cancer cells genetic programme to implode. The great area of interest with brain tumours is using common viruses that can deliver a chemical agent to kill a brain cancer cell, or using the viruses themselves to kill the cancer cell. (This is called virotherapy, and the viruses are called oncolytic viruses.) In both cases, the theory runs, that adjacent, healthy cells will be left unharmed.  Work is taking place in Universities from Edinburgh to Texas.

 

The most widely studied conditional cytotoxic transgene is Herpes Simplex Type 1 thymidine kinase (TK), which converts the prodrug ganciclovir (or valcyclovir) into the highly toxic deoxyguanosine triphotsphate causing early chain termination of nascent DNA strands. This approach has been widely studied using either adenoviral or retroviral vectors in numerous clinical trials in the U.S. and Europe and has demonstrated modest increases in median survival.  In April 2009, the U.K. based Ark Therapeutics released an update on promising results from a multi-center Phase III clinical trial using a first-generation adenoviral vector encoding TK (Cerepro) (Ark Therapeutics, 2009; Osborne, 2008). Unfortunately, the European Medicines Agency (EMEA) recently rejected Ark Therapeuticss marketing application after deciding that the study was statistically underpowered and failed to show sufficient efficacy in terms of postponing death or re-intervention. The decision by the EMEA is currently under appeal by Ark Therapeutics.

 

In fact we have covered many of these ’new’ therapies for more than 6 years!!