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Supervisors: Dr Jonathan Chee

Cancer immunotherapy such as blocking checkpoint inhibitors remove negative regulators of immune cells, unleashing them to target and kill cancer cells. However, unwanted side effects are collateral tissue damage caused by the immune system, which are termed immune related adverse events (IRAE). IRAE can affect different tissues and organs, and their immunopathology can be highly similar to some autoimmune diseases. Approximately 80% of treated patients develop some form of IRAE, and they vary in severity. In rare instances, they can be life changing or threatening. Understanding why IRAEs develop is important to improve cancer immunotherapy, and will likely inform the aetiology of autoimmune diseases.

We propose that biological mechanisms driving organ autoimmunity and tumour immunity locally will provide the breakthrough needed for rational selection of intervention drugs that can uncouple them. However, it is challenging to collect longitudinal tissue biopsies of IRAE affected organs from humans. We developed a suite of unique preclinical models that exhibit a range of anti-tumour immune responses and organ autoimmunity in the same animal when treated with immunotherapy. The aim of this project is to characterise differences in immune cells between autoimmune affected organs and tumours from the same animal. This project involves animal work, cell culture, organ and tumour digest, and immunology techniques such as flow cytometry, single cell and bulk RNA sequencing.

Open to:

• Honours
• Masters
• PhD

Supervisors: Dr Jonathan Chee

Immunotherapy blocking checkpoint inhibitors can lead to long-term tumour regression in a minority of cancer patients. Combining this immunotherapy and chemotherapy is an exciting treatment for mesothelioma because it can lead to durable tumour regression in some patients. However, it is unclear why majority of treated patients do not benefit from combination therapy. Furthermore, combination therapy is expensive, and can cause side effects. Our research focuses on understanding the immune mechanisms that underlie responses/non-responses to chemo-immunotherapy. By understanding why some patients benefit but others do not will help us develop novel strategies to improve responses to chemo-immunotherapy, and  develop novel predictors that can inform therapy decisions for cancer patients.

This project will map dynamic changes in antigen receptors, and gene expression of individual immune cells from peripheral blood samples of individuals undergoing combination chemotherapy and immunotherapy, relating these changes to treatment outcome and side effects. The aim of the project is to identify novel targets that can be further tested to improve chemo-immunotherapy, and potential novel biomarkers of response. The project involves animal models, and data analysis of sequencing data derived from patient samples.

Open to: 

• Honours
• Masters
• PhD

Supervisors: Dr Jonathan Chee

The immune system plays an important role in fighting cancer. Cancer immunotherapy is a promising treatment for an asbestos induced cancer, mesothelioma. However, not all treated patients benefit from immunotherapy. Retrospective studies implicate that usage of cholesterol lowering drugs (statins) is linked with immunotherapy benefit for patients with mesothelioma. This project will investigate how statins affect the anti-tumour immune response.

We discovered that regulatory immune (T) cells in mesothelioma tumours resistant to immunotherapy increased cholesterol metabolism genes. As cholesterol metabolism is important for regulatory T cell function, our study aims to test how commonly used statins in the clinic changes regulatory T cell functions such as proliferation, differentiation and cytokine secretion in vitro. Techniques include flow cytometry, immunoassays and cell culture. If successful, it will provide rationale to test statins in combination with immunotherapy in murine models of cancer.

References: Eur J Cancer. 2021 Feb;144:41-48. doi: 10.1016/j.ejca.2020.10.031

Open to: 

• Honours
• Masters
• PhD

Supervisors: Prof Jenette Creaney, Dr Alistair Cook

Cancer cells have developed many strategies to avoid being killed by both the host immune system and by cytotoxic assaults, such as chemotherapy and radiotherapy. Many studies have examined how cancer cells develop resistance to programmed cell death pathways such as apoptosis, and to the newly described ferroptopic pathway.

Ferroptosis is a form of regulated cell death caused by reactive oxygen species and associated with iron accumulation and lipid peroxidation. Ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. Recently, it was shown that ferroptosis plays a crucial role in radiotherapy-induced cell death. Radiotherapy kills tumour cells by both directly inducing DNA damage and by generating reactive oxygen species (ROS). Thus resistance to ferroptosis and insensitivity to radiotherapy are intrinsically linked.

Our laboratory at the National Centre for Asbestos Related disease focuses on mesothelioma, a uniformly fatal malignancy associated with asbestos exposure. The median survival for patients following diagnosis is approximately 12 months with only 5% surviving to 5 years. Mesothelioma is well recognised as being refractory to treatment and even the majority of patients do not respond to the recently adopted checkpoint inhibitor (ICI) immunotherapy. In this project we will use our established and well characterised mesothelioma models to investigate the therapeutic implications of targeting ferroptosis to overcome tumour radioresistance, the possibility of using ferroptosis regulators as potential predictive markers for radiotherapy efficacy, and the relevance of ferroptosis to radiotherapy combined with immunotherapy.

Open to: 

• Honours

Supervisors: Prof Jenette Creaney, Dr Melvin Chin

Mesothelioma is a rare, asbestos induced cancer and in Australia there are approximately 700 people diagnosed each year. Like many other cancers, immunotherapy has recently been approved for use in mesothelioma. However, the majority of patients do not respond to this treatment and chemotherapy remains an important option for treating patients. Despite decades of chemotherapy usage, little is known about which mesothelioma patients will benefit most from this treatment. The availability of large data sets across multiple cancer types provides our research team with an opportunity to leverage our own data generated from the Western Australian mesothelioma patient cohort to identify biomarkers to predict which patients will respond and equally important, not respond to a given chemotherapy agent. We have developed a model system in which mesothelioma cells have, by being exposed to increasing quantities of drug, become resistant to some chemotherapy agents. In these resistant cells we have preliminary evidence of alterations in some of the cellular pathways involved with cellular metabolism and cell death pathways.

In this project, bioinformatic analysis of DNA and RNA sequence data will identify mechanisms of chemotherapy resistance in mesothelioma. There is the potential to validate findings in either in vitro cultured human cell lines established from clinical samples, or in biospecimens from our extensive patient tumour biobank.

Open to: 

• Honours

Supervisors: Dr Alistair Cook

Recent work in our lab has examined how radiotherapy is able to modulate the immune system in ways that could potentially improve anti-tumour responses. Results from gene expression analysis has suggested that low doses of tumour-targeting radiation can alter the types of macrophages that are found within the tumour. We wish to examine this phenomenon in more detail, with a particular focus on detailed phenotypic changes, mechanisms of action, and how these cells interact with T cells with respect to immune checkpoint inhibitors. This project will primarily use tissue staining immunofluorescence from sectioned mouse tumours, plus flow cytometry, to gather these data.

Open to: 

• Honours

Supervisors: Dr Jonathan Chee, Dr Jesse Armitage

Adaptive immunity is predicated on specificity. Immune (T/B) cells respond specifically to target antigens, such as cancer, viral of self-protein. Immune specificity is attributed to the antigen receptors of T/B cells. To generate a repertoire of immune cells capable of responding to different insults, our immune system generates a diverse set (10⁶-10⁸) of T cell clones that each possess a unique antigen receptor. High-throughput sequencing allows us to study millions of these antigen receptors in parallel. We have sequenced antigen receptors of T cells in different disease models. This project will utilise bioinformatics tool to investigate if there are features of antigen receptor sequences that predict cancer therapy outcomes, or organ pathology in autoimmune disease.

Open to: 

• Masters

Supervisors: Prof Jenette Creaney, Dr Melvin Chin

Asbestos-induced mesothelioma is an aggressive and fatal cancer. There are two types of mesothelioma; epithelioid and sarcomatoid, which have different clinical characteristics. Epithelioid mesothelioma is more common, and untreated has a significantly better prognosis than the sarcomatoid sub-type. Interestingly however, sarcomatoid mesothelioma appears more resistant to chemotherapy and more sensitive to immune-checkpoint blockade treatments than epithelioid tumours. However, most treatment responses are transient. We have shown using patient derived cell-lines that it is possible, in the laboratory, to change the phenotype of mesothelioma cells from epithelioid-like to sarcomatoid-like, and that some cell lines exist in a hybrid phenotypic state between the two. The ability therefore to alter the phenotype of mesothelioma cells offers the possibility of increasing treatment options for patients.

In this project we will perform a bioinformatic analysis of both cell line and patient derived RNA data to characterise changes associated with phenotype-switching. The aim is to identify the drivers of phenotype-switching that could be targeted. There is the potential to validate findings in either in vitro cultured human cell lines established from clinical samples, or in biospecimens from our extensive patient tumour biobank.

Open to: 

• Honours

Supervisors: Dr Jonathan Chee, Dr Kofi Stevens

Mesothelioma is an incurable cancer. While new therapies that increase anti-cancer immune responses have shown promise, most patients do not benefit from immunotherapy.

Metals such as copper accumulate in mesothelioma, are essential for tumour growth and help cancers evade the immune response. Using copper-binding drugs, we aim to reduce the copper available to the cancer, and understand how it improves the function of anti-cancer immune cells. We will investigate the changes in gene and protein expression of tumour cells in response to copper and copper chelation therapy. Additionally we will characterise the effect of treatments on immune cell (T cells and macrophages) activity in-vitro. We will assess T cell mediated killing of tumour cells using in-vitro coculture assays in the presence of copper chelation therapies. Finally, we will determine the activity of copper chelation therapies in-vivo, and their effect on the tumour microenvironment.

As these copper-binders are clinically approved for use in other diseases, they are novel drugs that can be repurposed to improve immunotherapies for patients with mesothelioma.

Open to: 

• Honours
• Masters
• PhD

Supervisors: A/Prof Alec Redwood, Prof Jenette Creaney, Prof Bruce Robinson

Background. The ability of the immune system to recognise and control cancer has been known for more than 100 years and is the basis of recent successful cancer immunotherapies. Whilst, these immunotherapies, such as checkpoint blockade (CPB), have revolutionized cancer treatment, they work in only a small subset of patients. Therefore, alternative or synergistic strategies are required. Our laboratory is seeking to use cancer vaccines to treat patients either as a stand-alone therapy, or as an adjunct to conventional immunotherapies. During cancer progression the T cells that recognise cancer antigens become increasingly “exhausted”. This T cell exhaustion is reversed by CPB, however we do not know if vaccination also reverses T cell exhaustion

Design. We have shown that precursor non-exhausted (stem-like) T cell frequency correlates with positive outcomes in lung cancer and mesothelioma patients. This finding will be investigated in this study.

Aim 1 Determine the antigen specificity of stem-like T cells in cancer patients.

Aim 2 In an animal model determine if vaccination can reverse T cell exhaustion.

Techniques. Tetramer staining, ELISpot assays, mouse models vaccine studies.

Outcomes This study will determine the antigen specificity of exhausted and stem-like T cells in cancer patients. And in an animal model determine under what conditions T cell exhaustion can be reversed. It could lead to more effective vaccines for cancer patients.

Open to: 

• Honours

Supervisors: A/Prof Alec Redwood, Prof Jenette Creaney, Prof Bruce Robinson

Background. The ability of the immune system to recognise and control cancer has been known for more than 100 years and is the basis of recent successful cancer immunotherapies. Whilst, these immunotherapies, such as immune checkpoint blockade, have revolutionized cancer treatment, they work in only a small subset of patients. Therefore, alternative or synergistic strategies are required. Our laboratory is seeking to use cancer vaccines to treat patients either as a stand-alone therapy or as an adjunct to conventional immunotherapies. Cancer vaccines target altered proteins (neoantigens) that are derived from tumour specific mutations. Therefore, cancer vaccines turn a cancer’s strength, it’s mutations, into a weakness, as targets for immune cells.

Design. In this project you will use human samples to understand the T cell responses to neoantigens in lung cancer and mesothelioma patients.

Aim 1 Determine the diversity of the anti-cancer T cell response.

Aim 2 Define the T cell receptors used to recognise mutated human proteins.

Techniques. Single cell TCR sequencing, bioinformatics, TCR cloning. T cell reporter assays.

Outcomes This study will define the diversity of the TCR usage in cancer patients and will use TCR cloning to verify the specificity of these TCRs allowing for latter 3-dimensional crystal structure analysis.mFrom these studies we may be able to design novel, more effective cancer vaccines.

Open to: 

• Honours

Supervisors: Prof Jenette Creaney, A/Prof Alec Redwood, Prof Bruce Robinson

Immunotherapy is the most exciting development for many years for the treatment of cancer. But to make it work better we need to understand the underlying events, especially the relationship between the cancer cells and the immune cells. Pleural effusions provide a special opportunity to do that in patients with pulmonary malignancies.

For lung cancer patients presenting with a malignant pleural effusion (MPE) traditionally median survival was less than 6 months. The recent introduction of immune checkpoint inhibitor (ICI) therapy has expanded the treatment options available to this cohort, but little is known about the efficacy of ICI in this patient population and which patients benefit from this treatment. Given the unmet clinical need more research is required in this group to assist in clinical decision making.

Open to: 

• MD3 (2024)

Supervisors: Prof Jenette Creaney, A/Prof Alec Redwood, Prof Bruce Robinson

Immunotherapy is the most exciting development for many years for the treatment of cancer. But to make it work better we need to understand the underlying events, especially the relationship between the cancer cells and the immune cells. Pleural effusions provide a special opportunity to do that in patients with pulmonary malignancies.

Mesothelioma is an incurable asbestos-induced cancer. WA has the highest incidence of this disease in the world. Mesothelioma patients presenting with a malignant pleural effusion (MPE) and the recent introduction of immune checkpoint inhibitor (ICI) therapy has expanded the treatment options available to this cohort. However, little is known about the efficacy of ICI in this patient population and which patients benefit from this treatment. Given the unmet clinical need more research is required in this group to assist in clinical decision making.

Open to: 

• MD3 (2024)