Read about our recent cancer research.
Conventional T cells are capable of eliminating tumours by recognising unique or mutated proteins in the tumour tissue. In contrast, some T cells recognise other molecular structures, such as lipids, carbohydrates and metabolites. These cells are often described as ‘innate-like’ T cells, because they are always in a partially activated state so that they can respond immediately to stimulation.
An example is iNKT cells (invariant natural killer T cells), which respond to glycolipids like alpha-GalCer.
“Over the years we have accumulated strong evidence that these cells can be exploited to enhance responses to vaccination,” says Professor Ian Hermans. “Together with collaborators at Callaghan Innovation Research Limited, led by Dr Gavin Painter, we have now used this information to generate completely synthetic vaccines, with the intention of making off-the-shelf treatments for cancer.”
This work has been funded by the Ministry of Business, Innovation and Employment (MBIE), and has resulted in three patent applications and one PCT application.
Professor Hermans says there is still more work to do to fully optimise the vaccines, but it is hoped that one day we will see them tested in patients in New Zealand.
Painter GF, Johnston K, Anderson RJ, Compton BJ, Hayman CM, Hermans IF, Larsen DS (2013) Sphingoglycolipid Analogues. NZ611741
Painter GF, Anderson RJ, Compton BJ, Hayman CM, Hermans IF, Larsen DS (2012) Conjugate Compounds. NZ604085
Painter GF, Anderson RJ, Compton BJ, Hayman CM, Hermans IF, Larsen DS (2012) Organic Compounds. NZ601473
Professor Mike Berridge leads a research programme investigating the role of mitochondria – the energy powerhouses of our cells – in cancer and other diseases.
“Defective energy production for growth, brain function and movement contributes to numerous health problems,” says Professor Berridge. “At least 200 human diseases are reported to be due to mitochondrial gene mutations.”
Understanding the involvement of mitochondrial gene mutations in disease is difficult because there are currently no tools available to manipulate mitochondrial DNA in cells. The ultimate goal is to replace mitochondrial genomes in cells with custom-designed synthetic genomes, thus opening the door to a new field of targeted mitochondrial genetics.
Underpinning this work is Professor Berridge’s research investigating the involvement of the mitochondrial genome in tumourigenesis and metastasis. “We have shown that mitochondrial energy production is essential for tumour formation and metastasis. Thus, highly metastatic melanoma and breast cancer cells lacking a mitochondrial genome are unable to form tumours, until they acquire a mitochondrial genome from cells in their local microenvironment.”
Professor Berridge’s group is also exploring a range of tumour models to determine the physiological mechanism(s) of intercellular mitochondrial genome transfer.
“We have developed stable cell lines from each stage of this metastatic progression including primary tumour, circulating tumour cells and lung metastasis, allowing us to explore the role of the microenvironment in driving metastatic progression.”
These novel discoveries highlight the role of the tumour microenvironment in regulating tumour growth and metastasis.
Our Cancer Cell Biology researchers are undertaking a study that Group Leader, Professor Mike Berridge describes as “a world-first”. They are investigating whether DNA can transfer between cells damaged in bone marrow transplants.
“Using our cancer model, we showed that a damaged cell could collect fresh mitochondria from the host organism – there was a transfer of DNA,” said Dr Melanie McConnell, Malaghan Institute Research Associate and Senior Lecturer at Victoria University. The team soon realised that a similar situation occurred in bone marrow transplants. There, a patient is given therapies to suppress the growth of abnormally proliferating cells, before receiving replacement bone marrow from a donor. The result is that a transplant recipient could be left with two different types of mitochondrial DNA – their own, and that of the donor.
Using the differences between these mitochondrial DNA–there are about 40 base differences between any two humans – Prof Berridge and his research group aim to investigate whether genes travel between cells in order to replace those damaged in bone marrow transplants that include cancer. Eight donor-recipient pairs will be involved in this ground-breaking study: Samples of each participant’s bone marrow will be taken before, and again three months after transplantation. The aim of this is to examine whether any donor mitochondrial DNA markers are present in the recipient’s bone marrow.
In parallel, the team will investigate mitochondrial transfer in mice that have been treated with radiation – similar to that used in cancer treatment – which induces damage in the bone marrow. “We work with mouse models as it allows us to carefully design our experiments,” explains Prof Berridge, “…and to probe for genetic differences, we are using DNA sequencing and bioinformatics.”
Combined, these studies will provide a unique insight into the mechanism behind DNA transfer, and may have an impact on future treatment choices.
Professor Ian Hermans, Vaccine Therapy Programme Leader, and Dr Robert Weinkove, Wade Thompson Clinical Research Fellow and Clinical Director of the Human Immunology Lab, are establishing a research group that will bring cutting-edge new cellular therapies into New Zealand. This research involves a breakthrough area of oncology called CAR-T cell immunotherapy.
In this transfusion-like therapy, some of the patient’s own immune cells, the ‘T cells’, are modified to express a specific receptor – a chimeric antigen receptor (CAR) – in order to redirect them against cancer cells. “The approach works differently to vaccines, which aim to boost someone’s own immune response,” explains Dr Weinkove. “Here, we’re directly altering the immune cells themselves to target them.”
Central to the success of this new translational research is the expertise and knowledge of our team in good manufacturing practice (GMP) – international regulations for the production of medicinal products. “Our collaborators have developed an exciting pipeline of CAR-T cell therapies, our role is to make changes to the way they are manufactured and trialled, so that it fits with what’s regarded in the Western regulatory environment as ‘best practise’,” Prof Hermans explained.
For us at the Malaghan Institute, the driving motivation behind this project is the impact that it could have on the lives of New Zealanders. “For some leukaemias, more than half of people treated with CAR-T cell therapies have remained in remission for years without any other treatment,” Dr Weinkove said. “This is preliminary data, and we still have questions about the longer term effects, but as a clinician, I am extremely excited about the potential of CAR-T cell therapies.”
In 2015 a company, Avalia Immunotherapies Ltd, has been formed to commercialise the novel synthetic vaccine technology created by the long-term collaboration between the Malaghan and Ferrier Research Institutes.
The vaccine technology is the product of a ten-year research and development collaboration between immunologists at the Malaghan Institute, led by Professor Ian Hermans, and chemists at the Ferrier Research Institute, led by Professor Gavin Painter.
Professor Hermans believes the creation of the company recognises that the synthetic vaccine project has progressed beyond the discovery phase and now needs a defined structure and different expertise as it moves into commercialisation and Phase I clinical trials.
The company’s Chief Executive Officer, Dr Shivali Gulab, Victoria Link Ltd, says significant investment for pre-clinical evaluation and refinement of the product is now needed.
“To get our vaccine through the ‘valley of death’ from academic discovery to the market via human clinical trials, we need specialised acumen and expertise. Avalia provides a vehicle for us to package and develop the technology and to attract private and public investment,” she says.
The vaccine technology has been fully developed in New Zealand, meshing existing chemistry, immunology, drug manufacture and clinical trial expertise from throughout the country.
“We’ve made the original discovery and developed the intellectual property in New Zealand, but to license it offshore at this stage would mean the loss of potential major economic benefits. Of course, we have to take on more risk, but there is a significant opportunity to build our biotechnology expertise locally. This base would then be available to help develop other technologies and potentially support the creation of a new biotechnology hub here in the future."
The new vaccine technology has been patented. Although the vaccines have been developed to target cancer, the technology is also applicable to any disease where a strong T cell response is beneficial.
“The most effective way – perhaps the only way – for us to have an impact on health is to have a pharmaceutical company partner with us to progress the vaccine concept through later stage clinical trials. If we can undertake more of the development here, such as Phase I trials, then New Zealand will gain greater benefit from the significant investment we’ve already made.”
Avalia was founded by the Malaghan and Ferrier Research Institutes in combination with Powerhouse and the New Zealand Venture Investment Fund.
Vaccines traditionally have two separate components: an antigen (such as a protein fragment) that stimulates an immune response, and an adjuvant, a chemical that magnifies the body’s response to the protein fragment.
The vaccines being developed for commercialisation by Avalia Immunotherapies are delivered with these two components physically linked together, which makes them extremely effective. Once they reach the right location in the body the components separate and initiate an immune response.
“Some modes of activity are quite standard in the pharmaceutical industry,” says Professor Ian Hermans, “so you can make a lot of assumptions about how your drug is working at a cellular level.”
This vaccine, however, has a completely new mode of activity. If it were successfully commercialised, it would be the first of its kind.
“It’s unusual in that it relies on a series of molecular and cellular interactions that happen one after the other. Once delivered to key cells in the lymph nodes, the vaccine triggers activity from a second cell type. This cell then oversees the activation of a third, the T cell, which is sent to kill the tumour.”
Although the vaccine’s action is well understood in animals, it must be shown to work in the same way in humans before being allowed to progress to a clinical trial.
“There is no precedent for what we are doing with this vaccine – it’s completely new. Although all the cell types involved are found in humans, their distribution and number is different to the animals we have been studying. Our first goal therefore is to collect evidence that the concept will work in patients, and the next step is to find out which patients would benefit the most from it.”
Professor Mike Berridge and his Griffith University collaborators recently published a review of the field of mitochondrial transfer between cells, which he says puts the Malaghan Institute’s work into the context of other research internationally.
“These invitation to review the field was made on the back of the major contribution we’ve made, showing that mitochondrial DNA was transferred between cells in animal tumour models.”
The original paper was reviewed in Nature Reviews Cancer, the world’s top cancer journal, and been highly cited and downloaded several hundred times in its first six months.
Professor Berridge believes the mitochondrial transfer process is novel and fascinating from an academic perspective, but also has relevance to understanding the physiology and pathology of a raft of different diseases.
“It’s a real opportunity for the Institute to become involved as pioneers in a new research area that relates to brain function, the development of cancer, aging, degenerative diseases and aspects of early life and development.”
Berridge MV, Dong L, Neuzil J (2015) Mitochondrial DNA in tumour initiation, progression and metastasis: role of horizontal mtDNA transfer. Cancer Research 75: 3203–3208.
Dr Melanie McConnell, Malaghan Institute Research Associate and Senior Lecturer at Victoria University of Wellington, received funding of more than $1 million from the Health Research Council in 2015 to research the transfer of mitochondria between cells in the brain.
The project will look at the transfer mechanism in healthy and injured brain cells, as well as in cancerous glioblastoma multiforme cells.
“We’ve discovered this process of mitochondrial transfer and now we want to find out if it’s a normal process that occurs in response to damage and stress”, she says. “There’s a growing recognition that the way cells handle stress might be more sophisticated that we thought.” In the brain, neurons (nerve cells that transmit information through the body by chemical and physical messages) are surrounded and supported by star-shaped brain cells called astrocytes. Dr McConnell believes that astrocytes may donate their mitochondria as part of this support.
“We think the process may be important in helping neurons survive stress, with mitochondria from the astrocytes moving in to restore mitochondrial function in the vulnerable nerve cells.”
To model this process in the laboratory, brain cells are deliberately injured then tracked to study the effect on mitochondrial transfer and the consequence for the cell. Early results show much higher rates of transfer into an injured cell than an uninjured one.
Dr McConnell’s brain injury research models the effects of diseases such as Alzheimer’s and Parkinson’s.
“We’re looking at the chronic injury caused by genetic mutations associated with Alzheimer’s and other degenerative brain diseases. Understanding the processes that go on could be useful for developing new therapies for brain disease.”
The project is also studying the relationship between cancer cells and normal cells. In glioblastoma, a highly treatment-resistant brain cancer, the cancer cells may be using the same mitochondrial transfer mechanism to their advantage.
“Unlike the normal brain cells, these cancer cells are invulnerable. We are studying the mitochondrial transfer process to see if it has been changed in some way to give them this ability to resist treatment.”
In the experiment, glioblastoma cells were injured in the same way as normal brain cells, and mitochondrial transfer of the two types of cell was compared.
“We hypothesise that mitochondrial transfer increases cell survival. Obviously we want to encourage survival of a damaged normal cell, and to prevent survival after injuring a cancer cell. If we understand the process and work out how to manipulate it, we could change the balance between life and death for injured cells.”