Vaccine Group Current Research

Project One: Improving Vaccines with Compounds that Stimulate iNKT Cells

There is very little information in the literature regarding the different subpopulations of iNKT cells and the role they play in mediating immunity. One subpopulation contains the CD4 marker, while the other doesn't. We have shown that following stimulation CD4+ iNKT cells produce a significant quantity of IL-4 in vivo, which may influence the development of Th2 driven diseases such as asthma.

In 2007 we launched a new project in collaboration with Prof John Fraser from Auckland University, to exploit the potent immune-stimulating activity of superantigens to target tumour antigens to the dendritic cells. Preliminary findings suggest that this is a very effective way of getting the target antigen crosspresented to cells that mediate anti-tumour immunity. This approach generates much stronger anti-tumour immune responses with considerably less antigen.

It is now clear that the structure of the glycolipids presented to iNKT cells by dendritic cells can have a significant influence on their regulatory function. We are working with Dr Bridget Stocker, who heads the Immunoglycomics research at the Malaghan Institute, to investigate whether novel synthesised glycolipids can be used to promote iNKT cell activity and thus enhance immunity to tumours.

Project Two: Improving Dendritic Cell-based Vaccines for Cancer in a Laboratory Model

One of the main aims of our basic research programme is to increase the potency and efficacy of the dendritic cell-based vaccines so that we can stimulate strong, long-lasting anti-tumour immune responses. In 2007 we were successful in establishing an experimental model of the set-up used in our clinical trials, which will enable us to more directly test different ways of achieving this goal.

We have used this model to investigate whether Radiofrequency Ablation (RFA) treatment of tumours creates an environment that supports the generation of tumour-specific T cell responses. RFA is a novel technique that uses heat to destroy tumour cells in situ, while preserving surrounding tissue. We found that although RFA treatment was shown to delay tumour growth, a period of immunosuppression was observed immediately post RFA treatment and are currently investigating this further.

In other work, we have now shown that we can generate very strong prophylactic anti-tumour immune responses when our standard dendritic cell vaccine is used in combination with alphaGalCer (stimulates iNKT cells) and the depletion of T regulatory cells. These results complement our discovery last year that certain combinations of Toll-like receptor ligands improve dendritic cell activity and will be taken into consideration when formulating our clinical vaccine protocols.

Project Three: Using Dendritic Cell-based Vaccines in the Clinic

Since 2004 the Malaghan Institute has been involved in a phase III trial of a dendritic cell-based melanoma vaccine with the Queensland Institute of Medical Research and the Wellington Cancer Centre. It was anticipated that the trial would involve 200 patients from across New Zealand and Australia, however, a mid-point review of trial outcomes by an independent statistician sadly led to closure of the trial in 2007. It is important to emphasise that the trial wasn't stopped because it hadn't worked but because the number of patients involved in the trial was too small to show a statistically significant improvement in the health of the individuals being treated. Despite closure of the trial, New Zealand patients involved in the study have opted to continue receiving the vaccine should their disease progress to stage IV.

We are now in the process of reformulating the original vaccine protocol based on promising new data from our basic research programme and are seeking approval to test this in a phase I trial for patients with stage IV melanoma.

In 2007 we also completed our protocol validation studies into the development of dendritic cell-based vaccines for the treatment of glioma (brain cancer) and are awaiting ethics approval to launch the trial proper.

Clinical Relevance and Future Direction

In the future it is hoped that immunotherapy will be considered a conventional treatment that is used in combination with surgery, chemotherapy and radiotherapy to treat cancer. At present, immunotherapy as a stand-alone treatment for cancer may only be effective in a small number of patients. However, the real promise of this therapy is likely to be when it is appropriately sequenced with current ‘standard' therapies.

One treatment scenario would be to use surgery to debulk a tumour, radiotherapy and chemotherapy to attack disease at distant sites, and immunotherapy to mount an anti-tumour immune response against residual cancer cells. It is anticipated that the specificity and potency of immunotherapy will work in synergy with current cancer treatments, with the added advantage of reduced side effects and minimal discomfort to the patient being treated.

Designer therapies will be required for individual cancer patients because every tumour is different. Clinical trials such as those being undertaken at the Malaghan Institute are therefore crucial to establishing whether tailor-made anti-tumour vaccines can be effective. If so, there may be exciting opportunities to incorporate these vaccines with other carefully selected treatments appropriate to a patient's particular cancer.

Collaborators

Prof Vincenzo Cerundolo, University of Oxford, UK
Dr Sarah Hook, Department of Pharmacy, University of Otago, Dunedin, New Zealand
Mr Martin Hunn, Neurosurgeon, Wellington Hospital, New Zealand
Dr Gavin Painter, Industrial Research Limited, Wellington, New Zealand
Dr Chris Schmidt, Queensland Institute of Medical Research, Australia