Research Report 2016 - Vaccine Therapy
Our cancer vaccine therapies are being developed to induce strong immune responses by ‘programming’ the formation of large populations of T cells to fight disease. The new immunotherapy cancer drugs (Opdivo and Keytruda), which were approved for use in New Zealand this year, work using a different mechanism – they prevent cancer cells from turning any anti-cancer T cells off. Both approaches promise gentler, more effective treatments, although more research is needed to make them better.
While our vaccine development programme started by creating therapies for cancer, they are now being assessed in infectious diseases and even allergies. (Patent protection for these discoveries is in progress.) This work with the Ferrier Research Institute at the Victoria University of Wellington has been running since 2006 and combines their expertise in chemistry with our immunology capability.
A research grant from the MBIE Contestable Research Fund, valued at $9 million over five years, was announced in September to support the vaccine therapy programme. The funding will enable continued collaboration between the Malaghan and Ferrier Research Institutes, and also involves the Universities of Auckland and Otago to progress new therapies to market.
Associate Professor Ian Hermans, Leader of the Malaghan Institute’s vaccine therapy programme, welcomed the news.
“We’re a big part of this. Although we have all been working together for a number of years, this new funding is crucial for the next steps. Our research will look at different ways to make the vaccines programme T cells, which include new methods to get more of the vaccine into the appropriate cells, and new chemical structures that enhance the right sort of cellular interactions,” he says.
The programme will take a three-pronged approach to creating a stronger T cell response and therefore a more effective vaccine: increase the uptake of vaccine into the dendritic cells (these are the ‘generals’ of the immune army), ensure that the dendritic cells are stimulated to function properly and activate cells around the dendritic cells to create the right environment to encourage programming of T cells.
This combined approach is focussed on getting the T cells to recognise small fragments (called peptides) of tumour associated proteins that are displayed on the surface of the cancer cells.
“We look for a protein that’s been over-expressed or is mutated in cancer, find out what peptides are displayed on the cell surface, and then make these peptides synthetically to include in the vaccine. It's the job of dendritic cells to programme T cells to recognise these peptides.”
Expertise in peptide chemistry is crucial and is being provided by Professors Margaret Brimble (University of Auckland) and Gavin Painter (Ferrier Research Institute) and their teams. The concept of getting more antigen into the cells is being addressed in work by Professors Brimble and Rod Dunbar (also University of Auckland).
“They have shown that if the vaccine is decorated with the right carbohydrate molecules, you can selectively target the receptors on dendritic cells that will recognise, bind to the peptide and take it into the cell, drawing it in and soaking up more peptide – it’s very clever.”
CLINICAL TRIAL PROGRESS
Results from the Phase I safety and dosage clinical trial of our cellular melanoma vaccine are now in the final stages of statistical analysis and a manuscript for publication is being prepared. This vaccine involves modifying dendritic cells from a patient’s blood so they trigger an immune response to a protein found only in tumour tissue. The cells are grown and processed in the lab then returned to the patient.
Recruitment for a larger Phase II trial to examine the size and the quality of generated immune responses is also underway.
“We are well into the Phase II trial but are being held up by slow patient accrual and unplanned stops, but we recently employed Dr Alice Maxwell, another clinician at Wellington Hospital, to help recruit patients onto the trial.”
MAURICE WILKINS CENTRE PROJECTS
A project targeting hypoxic or oxygen-deprived regions of tissue is combining immunotherapy and chemotherapy for cancer treatment. Prodrugs are chemotherapeutic agents that are inactive until they reach a hypoxic region, where a trigger releases an active component that kills the hypoxic region and leaches out into the surrounding area.
“Hypoxia is thought to be a bad thing in cancer because it drives a lot of the immunosuppressive mechanisms that tumours use as they get bigger. For example, hypoxia brings in macrophages that swamp the T cell responses and stops them from functioning. Our hypothesis is that if you have a drug that focuses on eradicating the hypoxic regions, then it should help the immunotherapy work better.”
In another project, a novel chemotherapeutic agent developed by the Maurice Wilkins Centre is being trialled in our cancer models. The agent, a colony-stimulating factor (CSF-1) receptor inhibitor, has shown very promising results in vitro and attracted significant commercial interest.
“The first step is to make sure it works in vivo, then combine it with our vaccine therapy. The drug works by blocking macrophages, so it should be an anti-cancer agent on its own but it should also improve the activity of our immunotherapy.”
Assoc Prof Hermans would like to acknowledge the generous support of the Thompson Family Foundation for chemistry development at the Ferrier Research Institute and clinical trial support at Wellington Hospital.
Professor Ian Hermans
Dr Brigitta Mester, Ellie-May Jarvis, Kathryn Farrand, Ching-Wen Tang, Dr Nathaniel Dasyam, Dr Olivier Gasser, Emma Petley, Dr Mary Speir, Regan Fu, Olivia Burn, Evelyn Bauer, Joshua Lange.