Cookie policy: This site uses cookies to simplify and improve your usage and experience of this website. Cookies are small text files stored on the device you are using to access this website. For more information on how we use and manage cookies please take a look at our privacy and cookie policies. Your privacy is important to us and our policy is to neither share nor sell your personal information to any external organisation or party; nor to use behavioural analysis for advertising to you.

GIANT project aims to develop safe gene therapy for treating prostate cancer

Brussels, 13 Apr 2006

The detailed knowledge of the human genome has unlocked new opportunities for the treatment of disease. Gene therapy has so far proved to be a controversial as well as promising avenue of research, however. A European Union-funded collaborative project, 'Gene therapy: an Integrated Approach for Neoplastic Treatment' (GIANT), aims to make gene therapy both safer and fully acceptable for the clinical treatment of prostate cancer.

Before such therapies can be used clinically, fundamental problems - such as the limitation of vector dose, targeting and expression control, and decreasing non-specific toxicity - remain to be solved, requiring a broad range of disciplines. The coordinator of the project, Professor Norman Maitland, explains, 'building on the work of two projects on prostate cancer and one on viral vectors carried out under FP5, we've brought together prostate cancer experts, immunologists, viral vector and non-viral vectorologists'.

One of the reasons prostate cancer is a candidate for new therapies is that there is currently no effective treatment after relapse. The disease is second only to lung cancer as the cause of death to men in Europe, while its causes remain unknown. In addition, the rate of incidence has increased greatly since 1950. Though some of this increase may be attributable to improved detection, an estimated 150,000 cases now occur every year across the EU.

Over a five-year period, GIANT will receive over nine million euro of EU support as an Integrated Project under the Life sciences, genomics and biotechnology for health area of the Sixth Framework Programme (FP6). Oncologists will look into targeting the disease, while vectorologists focus on the design of delivery vehicles, or vectors, for the therapy.

A virus consists of a 'parcel' of genes 'wrapped up' in a protein coating. Viral vectors for delivering genetic therapies use cells in the human body as factories for replicating the active agent carried by the virus. Researchers developing non-viral vectors seek to 'mimic nature' by building a protein coating around the genes for delivery. One barrier to the use of non-viral vectors is that the immune system tends to react against them. The GIANT project brings together three European research groups on non-viral vectors and invited them to work on solving these problems for prostate cancer. 'After the first meeting we were all very encouraged. We're now looking for non-viral vectors highly specific to prostate cancers', affirms Professor Maitland.

'Sophisticated medicine is heading towards patient-specific treatments', says Professor Maitland, 'and prostate cancer is notorious for its heterogeneity'. The GIANT project aims to address this by developing several therapeutic agents in parallel, thereby hoping to produce an optimised set of vectors from which appropriate treatments can be selected.

Public acceptance is key to new techniques such as gene therapy. The project aims to communicate with patient support groups and open up 'closed' research groups to patients. There are benefits to this on both sides, says Dr Maitland: patients can listen and understand the commitment of researchers, who in turn tend to become more professional and motivated by the experience. In this area the project is working with the British Society for Gene Therapy (BSGT) and the European Society of Gene Therapy (ESGT), as well as the British Prostate Group of the National Cancer Research Institute. Professor Maitland emphasises the importance for young researchers of such exchanges, as well as the opportunities afforded by a European project for visiting other research groups in Europe, where a two-week stay can bring real understanding of other ways of working.

The EU Clinical Trials Directive requires the manufacturing of all Investigational Medicinal Products (IMPs) to the standards of Good Manufacturing Practice (GMP). The project consortium includes a GMP vector production facility and clinical facilities with scientific and ethical permission to carry out human cytotoxic gene therapy trials and aims to set up Phase I clinical trials in four countries: France, the Netherlands, Sweden and the UK. Phase I trials are aimed at demonstrating the safety, or non-toxicity, of a therapy, but in some cases they can also give indications of effectiveness in treating the disease. By combining four trials at once, says Dr Maitland, GIANT researchers hope to have results of statistical significance, giving some indications before going to the Phase II stage, of testing effectiveness through placebo controls.

While second and third-generation vectors are under investigation by the project, the clinical trials will only be on older, more established first-generation vectors. The GIANT participants have a long record of EU-based scientific collaboration and expertise in generating ethically approved clinical vectors. A Scientific Advisory Board of external experts has also been recruited to the project to advise on clinical trials and ethical considerations.

Without the significant EU investment behind a major project such as GIANT, it is unlikely that such a significant trial could be built, with all its potential benefits of producing effective new medicines, says Professor Maitland. He also emphasises that such a project does not represent public funding for the pharmaceutical industry, since the intellectual property rights (IPR) for all patented results will be owned by participating small and medium sized enterprises (SMEs) and academic institutions. Indeed, some of the SMEs participating already own patents on retargeting vectors and target discovery methods.

In terms of potential harm to the patient, expressing the right gene in the wrong place is as bad as expressing the wrong gene, warns Professor Maitland. The project is therefore taking a 'double targeting' approach. 'Attachment targeting' is based on the need for the virus to attach to the outside of a cell, so GIANT will look for specific receptors on the outside of prostate cancer cells to which viruses can attach. Meanwhile, 'expression targeting' aims to tailor the genes so that once in the cell they can only be expressed when in the presence of specific markers that only exist in prostate tumour cells.

Research at the forefront of medical science is becoming increasingly multidisciplinary. This brings its own challenges, such as experts in targeting trying to design delivery vectors as well. GIANT brings both sets of researchers together, says the professor, 'we say we need this target, they say if they can deliver it'.

The genes delivered by the vector are designed to cause cell death through a variety of means. For example, a virus could kill a cancer cell by growing and multiplying in it to excess, or it could insert a new gene into the cancer cell (this is called 'pro-drug activation') that only expresses itself and kills the cell in the presence of a second drug that is inert in rest of body.

The immune system often flushes vectors out through the liver, with associated dangers of organ overload. 'Stealthing' is a technique based on coating the virus to avoid this. One work package of the GIANT project will attempt to coat the virus in polymer, using a technique developed in the Czech Republic, so that it is inert to the immune system and flushed out in urine, rather than through the liver. The aim is also to make the virus 'non-sticky' to white blood cells, says Dr Maitland, and then put attachment chemicals, or surface antigens, on top of the coating to stick to cancer cells.

Predictive toxicology is of growing importance in developing innovative medicines. In order to avoid the over-reactions of the immune system associated with some gene therapy trials, extensive testing of the agents will be carried out in blood supply and healthy tissue. The team will also use 3D tissue reconstructions to test with multiple prostate tumour cell-types, as well as healthy tissues. Both will come from current patients rather than using old cell lines.

As a result, one of the outputs of the GIANT project should be to select candidates for testing in Phase I clinical studies, using a clinically approved vector backbone based on adenoviral constructs. While thorough testing means these therapies are still not close to market, the GIANT project aims to build a critical mass of expertise to accelerate innovation in this area.

GIANT project website

Further information on EU funded research in genomics and biotechnology for health

CORDIS RTD-NEWS/© European Communities, 2005
Item source

  • Print
  • Share
  • Save
  • Print
  • Share
  • Save
Jobs