Malignant Glioma immunotherapy by histone deacetylase inhibition administered by convection enhanced delivery.

Malignant gliomas are the most common primary cancerous brain tumour in adults and the leading cause of cancer death in children. Current treatment is non-curative and the prognosis remains very poor. Despite many advances in surgery, radiotherapy and new chemotherapies, the survival statistics of this disease has not significantly changed in the last 30 years. Because of this, many researchers are developing new techniques to try and improve the outlook for patients with malignant glioma.

One reason that standard chemotherapy is not as effective against malignant glioma when compared to cancers, is the inability for drugs to enter the brain in sufficient concentration when given though conventional systemic route (either orally or intravenously). Convection-enhanced delivery is a technique that allows us to infuse drugs directly into the brain through surgically implanted micro-catheters, and overcomes this problem. The technique is currently being used in patients in clinical studies, and my research will build on a wealth of experience using this technique developed by Professor Gill's functional neurosurgery research group at the University of Bristol.

Glioma cells have many changes within them that often make them resistant to standard chemotherapy. This is also the case with other malignancies that are difficult to treat. In health, abnormal cells that may have cancerous potential, are usually destroyed by the immune system, and never go on to produce tumours. There has therefore been considerable effort in cancer research to develop ways to manipulate the host immune system to try and kill tumours, whilst protecting normal non-cancerous cells. This immunotherapeutic approach has been shown to be effective in other difficult to treat cancers, such as melanoma, and is in advanced stages of investigation in patients.

There is now considerable evidence to suggest that immunotherapy may be effective in treating malignant glioma. We now know that that glioma cells create a microenvironment within the tumour that interacts with the immune system and effectively switches off the normal immune response to abnormal cells, and allows the tumour to grow. The techniques used in other cancers to 'reprogram' the immune system to fight off abnormal cells has been difficult to achieve in brain tumours because of the natural barrier between the brain and the blood-stream. Convection-enhanced delivery of drugs that are able to manipulate immune cells could theoretically change the environment around a brain tumour and promote the immune system to attack these glioma cells, leaving normal brain cells unaffected.

Panobinostat is a new anti-cancer drug that is known to manipulate the immune system in other cancers to cause tumour cell death. I will investigate the potential of this drug to manipulate immune system within the brain as a possible future treatment for this devastating disease. I will achieve this using the techniques already well established by Professor Gill's team in collaboration with the world-class facilities and training in immunology available from Professor Wraith and Wooldridge at the University of Bristol. It is my overall aim to produce a robust body of evidence to allow rapid translation of this therapy into a clinical trial using convection-enhanced delivery as a method of administration.

Malignant glioma carries a very poor prognosis with a median survival of 14.6 months in adults, despite multimodal therapy with cyto-reductive surgery and adjuvant chemoradiotherapy. Diffuse intrinsic pontine glioma in children carries an even worse prognosis with a median survival of 9 months and no effective current treatment. A new approach to treating this disease is required.

One significant problem with standard chemotherapy for these malignancies is the difficulty in achieving therapeutic doses in the central nervous system without causing significant systemic toxicity. Direct drug delivery to the brain using convection-enhanced delivery through sterotactically-inserted microcatheters overcomes this problem. In addition, once delivered, these therapies will not readily pass back into the systemic circulation, thereby limiting their systemic side effects.

Cellular immunotherapy is a novel approach in cancer therapy and is effective in other malignancies. The interplay between a malignant glioma and the immune system makes immunotherapy an attractive novel therapeutic option for this disease. The glioma microenvironment is immunosuppressive, which may account for why systemic immunotherapeutics are yet to show any clinical efficacy in glioma trials. CED may allow us to manipulate this to a therapeutic advantage by directly infusing immunomodulatory agents into the tumour itself.

Pan-histone deacetylase inhibition (HDACi) has shown to have immunomodulatory effects in other malignancies. Evidence suggests that it up regulates antigen expression via MHC class II and alters the cytokine profile within tumours. Moreover, the in vivo efficacy of this class of drug seems to require an intact immune system. I will investigate the efficacy of Panobinostat, a HDCAi, administered by CED to a brain tumour model and its ability to mobilise a T cell response, with an overall aim to translate this research into a clinical trial for patients with malignant glioma

Glioblastoma is the most common primary malignant brain tumour in adults, with a very poor survival despite advances in surgery, chemotherapy and radiotherapy. Diffuse intrinsic pontine glioma is another intrinsic glial cell derived malignancy that has an even poorer prognosis and is the leading cause of cancer death in children. There is no treatment currently that has an effect on prognosis. Direct drug delivery to the brain using convection-enhanced delivery could potentially revolutionise the treatment of both of these malignancies and improve the outlook for these patients. The most obvious impact of my research will be on the patients with this currently fatal condition. Results of my research will contribute to the advances in both the understanding of this disease, but most importantly the application of a novel treatment method.

The multiple academic beneficiaries from this research and how they will benefit are described above in 'academic beneficiaries'. This research will also impact on several other non-academic groups. As well as the overall aim to impact directly on patient care by delivering a novel therapeutic delivered with a novel technique, this research will have a wider impact:

1) Pharmaceutical and medical devices industry

My research aims to bring a new drug to clinical trial. I will investigate and develop an encapsulated micellar formulation of a water insoluble drug for direct infusion into the brain extracellular space. If successful, this could pave the way for other drugs with similar chemical properties, which have to date limited their clinical application, to be used with convection enhanced delivery, This would allow other drugs in development designed to treat a wide range of central nervous system diseases, not just malignant disease, to be translated to the clinic. This will also allow the medical devices industry involved in the design and manufacture of drug delivery systems to also benefit, as the technology could potentially be applied to a far wider range of CNS disease.

2) Other diseases where direct drug delivery is indicated.

As explained above, my research will investigate a novel formulation of a water insoluble drug. CED cannot deliver water insoluble drugs. The process of encapsulation into a water-soluble micelle has significant potential to deliver a wide range of therapeutic agents to the brain by CED. Therefore, drugs that would otherwise never make it to the clinic may now be a real option for patients with other malignant and non-malignant CNS disease. The principle of CED could also be applied to deliver compartmentalised therapy to other conditions outside the CNS where tumour surgery is not possible, or not effective.

More specifically to my research project, histone deacetylase inhibitors are in clinical trials for a number of other conditions, and will have a much larger impact on disease than just to malignant glioma. The development of an encapsulated water-soluble formulation of a member of this drug family in this research project may mean that it can be used in other conditions where a water-soluble intravenous preparation is required. This is particularly of relevance in paediatric medicine, where the administration of oral compounds is sometimes difficult.

Overall, it is anticipated that the output from my research will have an impact on a wide range of groups; including academics involved in cell biology, nanotechnology and translational biomedical research, the pharmaceutical and medical devices industry, clinicians, patients and their families.