Cancer Research UK's Chief Clinician Professor Peter Johnson and lead trial researcher Dr Penelope Brock at the press conference announcing the trial

Cancer in children is not common. And although this is something to be thankful for, it can make things a little more challenging for researchers. This is simply because if fewer people have a particular type of cancer then there are fewer people to take part in clinical trials.

To help overcome this hurdle, Cancer Research UK funds 20 childhood cancer clinical trial centres across Great Britain, linked together within the Children’s Cancer and Leukaemia Group (CCLG).  Our scientists also collaborate with research groups around the world to run international trials into childhood cancers.

And today, we announced the opening of an international clinical trial into neuroblastoma – a rare type of childhood cancer.

The trial is a perfect example of how research can bring pioneering new treatments to children with cancer in the UK – and is based on some really exciting scientific discoveries…

A new way to tackle neuroblastoma

Around 100 children are diagnosed with neuroblastoma in the UK each year – most of whom are under the age of five. The cancer grows from nerve cells ‘left over’ from the development of the nervous system, and often starts in the abdomen.

About half of all children with the disease have a more aggressive form called high-risk neuroblastoma. It’s these children who will be taking part in the new trial, which is testing a type of immunotherapy – a catch-all term used to describe treatments that use the power and precision of the body’s own immune system to fight disease.

In the new trial, patients will be given a type of molecule called a monoclonal antibody. These are proteins produced in the lab that can stick to particular molecules on the surface of cells – in this case, molecules called GD2 antigens that are found on the surface of neuroblastoma cells.

The antibodies are injected directly into the patient’s bloodstream, where they travel around the body and eventually encounter the tumour, and stick to the GD2 antigens on the cancer cells.

Once the cancer cells are ‘labelled’ in this way, the body’s immune system can recognise them – and destroy them.

A similar technique to the one being tested in the new trial has already shown exciting results in a US study, and until now the treatment has only been available in America.

As in most trials, the US study compared the outcome for two groups of patients – one receiving the new treatment and one the standard treatment. But the new antibody treatment was so promising that the trial was modified so that all children participating ended up receiving it.

The treatment is designed to be used after a child has been treated with a combination of surgery, chemotherapy and radiotherapy. These standard treatments eliminate most of the cancer cells, and then the highly targeted antibody should – in theory – encourage the child’s immune system to mop up any that remain.

The new trial will split participants into two groups. One will receive the antibody alone, and the other the antibody and another molecule called a cytokine.

Cytokines are molecules produced by the cells of the immune system. They act as signals that can attract more immune cells to a particular area. The theory is that the extra cytokine will encourage the immune system to mount a more powerful attack against the neuroblastoma cells.

All participants in the modified US trial received the antibody with one of two different cytokines, so this new trial is the first time treatment with the antibody alone has been tested. The new trial aims to discover which approach gives the best outcome for patients.

The promise of immunotherapy

Immunotherapy is an area that’s been under intense research for over a decade, and has shown promise in treating other types of cancer. The breast cancer drug Herceptin is another example of a monoclonal antibody-based treatment.

But as Cancer Research UK’s chief clinician Professor Peter Johnson explained, ‘this is the first time an antibody has been taken into treatment for childhood cancer.’

And it spells good news for children with aggressive neuroblastoma. At our press conference, Great Ormond Street Hospital’s Dr Penelope Brock, the lead researcher on the trial, said the rapid launch of this trial in the UK was really fantastic news for patients. ‘Early results from the US trial found that children who received the immunotherapy treatment had less chance of the disease coming back two years later, compared with patients who did not receive the antibody.’

The new trial means that children in the UK now have access to what Dr Brock says is ‘possibly the biggest breakthrough in neuroblastoma for a very long time.’ However, she also sounded a note of caution, saying that longer term outcomes are still not known and so further international trials will be necessary.

For uncommon cancers like neuroblastoma, international trials are vital for to ensure that enough participants are included to give accurate results. This trial aims to recruit 2000 patients from across Europe, including about 160 children with high-risk neuroblastoma from the UK. The team are hoping that nearly all eligible children in the UK will take part in the trial and receive the new treatment – the first two participants are starting their treatment this week.

Committed to childhood cancer research

Cancer Research UK is the largest funder of research into children’s cancers in the UK – we spent over £9 million last year on research in this area. For this latest trial, we are paying not only the running costs but also the cost of manufacturing the new treatment. This is because the drug is so cutting-edge that no pharmaceutical companies (that would usually supply drugs for a clinical trial) are yet involved.

We have also funded many of the world’s most successful trials of children’s cancer treatments, and more than three quarters of children with cancer in the UK now survive. Back in the 1960s, only a quarter of children survived – a testament to how investment in scientific research can ultimately improve treatment and care.

Nell Barrie, Science Information Officer

URO TODAY: Researchers have discovered that prostate tumours in mice can cause immune cells known as CD8+ T cells to change to cells that suppress immune responses. READ MORE>

This finding, by researchers at the US National Cancer Institute, has important implications for the design of immune-based therapies for cancer.

Future work by this team will focus on defining the mechanisms by which  gain their suppressive functions.

“This will enhance our ability to generate more effective anti-tumor T cell responses in mice, which then might be translated to human.”

URO TODAY: In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. READ MORE>

Current Trends in Immunotherapy and Vaccine Development for Viral Diseases of Fish

Scott LaPatra
Clear Springs Foods Buhl, ID, USA
Sharon Clouthier and Eric Anderson
Maine BioTek, Inc. Winterport, ME, USA

Introduction

Viral immunity and vaccine strategies designed to prevent or minimize the impact of diseases in intensive salmon and trout culture is intricate work requiring integration of biological and economic variance. These elements can be analyzed scientifically from a basic or applied approach with the latter approach being a conduit for the third element, the production, commercialization and use of the product to improve fish health. It is difficult to discern and integrate these elements during preliminary investigations, but for clarity it is useful to understand which stage of scientific research is being addressed by a particular experiment or experimental outline. Basic viral vaccine research in finfish aquaculture should not necessarily require a motive such as the development of a commercial product. Without this limitation, research continuity could be attained resulting in a deeper understanding of the host-pathogen interaction and the development of effective control strategies. In this chapter, some of each element will be addressed but the primary focus will be basic biology and a description of the importance and utility of using a model system for systematic analysis and comparison of therapeutics and vaccine types.

The process of vaccine research and development requires that the effect of an immunomodulator on viral pathogenesis can be measured experimentally. The performance of a vaccine or therapeutant is determined by measuring its potency, efficacy and safety performance using a well-defined experimental model system. A model system requires an understanding of the dynamics of interaction between the host, pathogen and environment. Points to consider when developing a model system include host range and susceptibility, virus strain characteristics, route and entry and progression of disease, virus load, water temperature and other environmental variables, as well as fish size, age and life stage. A well-characterized model system has been developed for infectious hematopoietic necrosis (IHN) virus, a pathogen of salmon and trout and a member of the family Rhabdoviridae and the genus Novirhabdovirus. The disease is most acute in young fry and mortalities can be as high as 100% in a given population.

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Current Trends in Immunotherapy and Vaccine Development for Bacterial Diseases of Fish

Kim D Thompson and Alexandra Adams
Institute of Aquaculture University of Stirling Stirling, FK9 4LA, UK

Introduction

Aquaculture fish production has increased significantly over the past few decades and with it the incidence of bacterial disease outbreaks, often associated with an intensification of the culture conditions. Bacterial disease causes substantial economic losses to the industry. Although antibiotics and chemotherapeutants are extensively used to control disease outbreaks, there is increasing concern about the use of these substances in aquaculture because of drug residues in food, the development of antimicrobial drug resistance, and the detrimental effect on water microbial ecosystems and populations. Increased attention is now being given to disease prevention as a means of controlling disease outbreaks based on improved husbandry and biological control methods such as vaccination and immunostimulation.

Vaccination, or immunoprophylaxis, is based on the principle that when a foreign organism, such as a bacterium or virus, invades it host, the animal’s immune response reacts against it in an attempt to remove it. If the fish is re-exposed to the same organism, the immune response is primed to response against it. This is referred to as a memory response or adaptive immunity. Vaccination mimics the invasion of pathogens and primes the animals’ immune system for re-encounter with the pathogen without causing disease.

The first published evidence that fish are able to elicit an immune response to bacterial pathogens dates back as far as 1935. Around this time, a number of authors showed that fish were able to produce antibodies against various bacterial fish pathogens. It was Duff, however, working with Aeromonas salmonicida, who first showed that the antibody response elicited by fish was capable of protecting the animal from disease outbreaks. It took another 30 years before vaccination was actually used as a means of controlling fish disease. Serious outbreaks of Enteric Redmouth (ERM) in rainbow trout (Oncorhynchus mykiss) farms in the Hagerman Valley in Idaho, USA, and Vibriosis in salmon farms nearby led to a renewed interest in the potential of fish vaccines.

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How can we make antibody treatment more effective?

It’s an exciting headline – “Potent cancer drug hopes raised” – but what’s the real story behind it?

This is research from scientists in Manchester, Southampton and Latvia, funded by Cancer Research UK, Leukaemia Research, the AICR, Tenovus, and the ECMC network and published in the Journal of Clinical Investigation.

In their paper, the researchers have found that some types of antibody can kill cancer cells in a new and unexpected way – by causing their internal ‘rubbish bins’ to overflow, literally flooding them with toxic ‘garbage’.

The results raise hopes for more effective treatments in the future – but we need to be careful not to get too excited, because there’s still a long way to go.

Antibody-based cancer drugs
Antibodies are proteins produced by the immune system, with the ability to recognise and stick to other proteins with a high degree of accuracy.  In the body, they are used to alert the immune system to the presence of invading bacteria or viruses.

In recent years, progress has been made in developing antibody-based treatments for cancer, such as the lymphoma drugs Rituximab and Herceptin.  Some of these treatments are extremely effective. For example, Rituximab has made a significant improvement to survival from non-Hodgkin lymphoma.

Although they work in a variety of ways, a common theme is that many antibody drugs alert the immune system to the presence of cancer.

Similar drugs, different effects

In theory, such antibody-based drugs should be similarly effective at killing cancer cells. But – intriguingly -  some are significantly more potent than others, with a more powerful cell-killing effect.

A research team led by Dr Mark Cragg and Professor Tim Illidge, wanted to find out the reason for this difference, because it could have a significant impact on the development of future antibody treatments.

So the researchers tested two experimental antibody drugs on human leukaemia and lymphoma cells that had been grown in the lab – tositumomab (also known as Bexxar) and one called L243.  These antibodies were chosen because they’d previously been shown to be particularly potent compared with other similar drugs including Rituximab.

The team  discovered that the antibodies caused the cancer cells to clump together and rapidly die, but in a most unexpected way – by flooding them with garbage.

Toxic overflow
Like any well-run city, a cell depends on efficient waste disposal to maintain a healthy environment. Inside the cell, waste products are kept within ‘waste disposal units’ called lysosomes. These are carefully sealed, to prevent their toxic contents from damaging important proteins and DNA within the cell.

When the cancer cells were treated with the antibodies, the researchers found that the lysosomes within them were literally exploding, pouring their contents out into the cells and causing rapid death.  Imagine a toxic waste swamp flooding a city, and you’ll have a pretty good idea of what’s going on.

Next steps
The fact that the Bexxar and L243 cause this dramatic effect explains why they are more potent than other antibodies (such as Rituximab) that alert the immune system but don’t directly cause cell death.

This knowledge is vital for researchers who are currently developing and testing antibody-based cancer treatments that direct the immune system to kill the tumour.  It suggests that the most potent antibodies will be those that can spark the ‘death by garbage’ response in cancer cells.

And there is another important twist. Many chemotherapy drugs work by tricking cancer cells into committing suicide by a completely different process, called ‘apoptosis’. But during treatment, tumours often evolve to turn off their apoptosis machinery, cheating death and leading to drug resistance.

But because these new antibodies provoke a different method of cell death, they may be useful for treating patients whose tumours have become resistant to chemo.

But it’s important not to get too excited just yet. Although these results are scientifically interesting – and will doubtless inform the development of more potent antibody treatments – there’s still a lot more work to be done.

Kat

PROSTABLOG NZ: A leading NZ scientist has discovered a novel compound he believes will suppress the prostate cancer that is killing him.

Dr James Watson (right) – a former professor at the University of California, now back in NZ – discovered too late he has advanced cancer, so has embarked (with a fellow Kiwi scientist, who also has advanced prostate cancer) on a research project to stop his deadly disease.

He believes he has identified a treatment that will stimulate his immune system to fight the cancer, which has spread beyond his prostate.

He has decided to test the compound on himself, with the assistance of another eminent Auckland medical specialist.

His quest is driven partly by the altruism of finding a viable treatment for all men whose prostate cancer moves to a stage that defies treatment, and partly by his anger at not being diagnosed early when the disease could have been treated easily.

He saw several GPs before one offered him a PSA test, by which time his level was a lethal 987.

He and colleague Dr Richard Forster, an expert on immunology and plant biology, have set up a company to develop their discoveries.

They revealed their progress at the annual conference of the NZ Prostate Cancer Foundation in Napier.

READ MORE>

JULY 27: PUB MED: A trial involving men with hormone-refractory (advanced) prostate cancer who were  treated with Provenge (a cellular immunotherapy product called Sipuleucel-T) had a “survival benefit” and only modest side effects, say the Washington researchers. READ MORE>

The integrated results…demonstrate a survival benefit for patients treated with sipuleucel-T compared with those treated with placebo.

The generally modest toxicity profile, coupled with the survival benefit, suggests a favorable risk-benefit ratio for sipuleucel-T in patients with advanced prostate cancer.

The most common adverse events associated with treatment were chills, pyrexia (fever), headache, asthenia (physical weakness), dyspnea (shortness of breath), vomiting, and tremor.

JULY 24: URO TODAY: Metastatic prostate cancer is an attractive target for radio-immunotherapy (RIT), as no effective therapies are available.

This review highlights the most important achievements within the last year in 3-D positron emission tomography (PET)/computed tomography (CT) and RIT. READ MORE>

JUNE 11: SEEKING ALPHA.COM: A groundbreaking new treatment for prostate cancer, Provenge, will likely receive US Food and Drug Administration approval and become widely available just as the first Baby Boomers reach 65 in 2010.  READ MORE>

JUNE 10: URO TODAY: Ongoing clinical trials the promise of immunotherapy for prostate cancer, but the precise role for immunotherapy remains to be determined. READ MORE>

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  A collaborative effort to develop and assess clinical strategies and biological assays for inducing, maintaining and monitoring tolerance in humans for transplantation, autoimmune diseases, and allergy and asthma. News on clinical trials.

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My gut tells me this “vaccine” is not a significant advance for men and families living through the nightmare of advanced prostate cancer.  I remain unconvinced that this is anything more than a GM-CSF effect (a key component of the ex-vivo therapy).  We all know this is not the silver bullet to beat the disease.  At best it is an incremental advance in PC.  But to many, it is a monumental advance because it pushes the agenda of immunotherapy into the limelight.  It would be the first “vaccine” therapy for cancer to gain such approval in cancer.  But of course it is not a “vaccine” in the traditional sense of the word either.

As a medical oncologist who treats advanced PC every day, I can tell you I work hard to use docetaxel sparingly.  It is far from a panacea.  Frankly, the careful use of hormone blockade (read intermittent therapy) can keep men with metastatic disease away from chemo for a long time.  Combine this with a knowledge of endocrinology (read estrogen, ketoconazole, anti-androgens) and we can keep men away from chemo for a very long time.  Mix in a healthy optimism for the future (read MVD3100 & Abiraterone) and I have more chances to keep men “chemo-naive”.

The current report shows a 4.1 month advantage (intent to treat) for Provenge but I have reservations.  Why, well first of all there was no docetaxel only arm.  This is a disease plagued by lead-time and length-time bias.  Sure that should drop out on analysis, but it screams for a comparison with docetaxel, the current standard of care.  Men continue to have improved survival with this disease due to early diagnosis, better therapy, and supportive care.  4.1 months will come at a very high financial cost.  A cost that Medicare cannot afford.

Others can point out the flawed studies given to ODAC in 2007, the Cancer Letter reports, and the lack of biologic endpoints.  Some will argue over just beating the pre-defined 22% reduction in risk of death.  But the bottom line is, this is not a blockbuster for PC.  This is not going to save lives.  I think Provenge will win approval on technical terms and on our failure to question the current system.  Industry, patients, immunologists, and advocates will not let it fail.  I cannot imagine the outrage if not approved.

The more I thought about this, I realize my concern is not with Provenge, it is with the way the FDA works.  Speaking as an optimist, I hope these difficult decisions bring about the needed re-evaluation of the process.