MRV has supported over 85 research projects.
Below is a collection of the more recent studies.
To see the lay summary of the project, as provided by the researchers – Please click on the ‘+’ next to the project titles to see more information
Researchers:
Ms Elinor Rees, Prof Caroline Dive, Dr Kathryn Simpson, Dr Rebecca Lee, Prof Paul Lorigan, Prof Sarah-Jane Dawson, Dr Stephen Wong, Dr Luissa Motta, Mr Derrick Morgan, A/Prof Shahneen Sandhu
Project:
Although only 4% of skin cancers are melanomas, they account for almost 50% of skin cancer deaths, making it a highly aggressive disease. Due to the many differences in the disease at early stages, it is difficult to predict which patients are going to relapse. It is therefore important to identify these patients in order to improve survival outcomes and avoid unnecessary therapy which can cause harm.
Using samples from the MRV, we plan to examine how melanoma cells, immune cells and other cells in the tumour interact and whether this is associated with the chance of melanoma returning. Using this knowledge, we will identify tests which can predict outcome for patients with early stage melanoma.
Researchers:
Prof Axel Kallies, A/Prof Shahneen Sandhu, A/Prof David Gyorki, Prof Grant McArthur
Project:
Cancer checkpoint inhibitor therapy relies on a small population of tumour infiltrating T cells with stem-like properties. In this project we will use patient tissue collected at the time of a lymph node dissection to identify the presence of ICB-responsive stem-like T cells that play a critical role in defining the patients response to ICB.
In parallel but separate from this application, we plan to undertake preclinical studies to target these T cells with stem-like properties to enhance cancer immunotherapy.
The combination of the clinical studies being proposed in this application taken in conjunction with our ongoing preclinical work will position us to undertake clinical studies in the future leveraging bench to bedside and bed side to bench research.
Researchers:
Dr Aparna Rao, Oxon
Project:
Immunotherapy has emerged as an important treatment option for patients with melanoma. Much of our knowledge about outcomes after treatment with immunotherapy comes from clinical trials, however understanding what happens to patients in the real world can also be very informative. In this study, we will contribute to a global study that will help to understand real world treatment patterns and clinical outcomes in patients who have been treated with anti-PD1 immunotherapy.
Researchers:
Prof Mark Shackleton, Dr Fumihito Noguchi
Project:
Melanoma is the fourth most common form of cancer and the most common cause of cancer related death in young adults (20-50yo). However, early melanoma has excellent outcomes, with more than 90% being cured with surgery alone. Current prevention of melanoma is passive, relying on public health messaging to reduce UVR exposure, and early detection in high-risk patients. There are no active treatments are used for melanoma prevention. In part, this is because the events that lead malignant transformation, whereby normal melanocytes (pigment producing skin cells) become melanomas, are poorly understood.
Experiments examining melanocytes in human skin and mouse skin suggest there may be a small subset of these cells driving this transformation from normal to melanoma. One candidate is a subset of cells with increased levels of a protein called NTRK2. These cells demonstrate properties characteristic of a cell with the potential to drive this malignant transformation and therefore could be a target for melanoma prevention. Moreover, reports of NTRK2-fusion genes in melanomas indicate that NTRK2 may play roles in melanoma progression too and thus could be a target for melanoma treatment. In this project we will investigate the expression of NTRK2 in human melanomas at specific clinical stages and test possible links between its expression and melanoma progression.
Our work will open opportunities to better understand the cells that drive melanoma formation and identify important targets for therapies to prevent melanoma formation or inhibit melanoma progression.
Researchers:
Dr Eyal Mor Hadar, A/Prof David Gyorki
Project:
This is a multicentred retrospective analysis of all patients who underwent lymphadenectomy for palpable metastatic melanoma and presented with features of high risk of recurrence and received adjuvant therapy. The aim is to assess the outcomes of adjuvant therapy on local control in these patients.
Researchers:
Dr Lorey Smith, Prof Grant McArthur, Dr Michael Clark, Prof Alicia Oshlack,
Project:
Human cells contain approximately 20,000 genes in the DNA, and these genes contain the information required to make proteins, the cell’s action molecules and building blocks. Intriguingly, there are many more proteins in our cells than there are genes, which helps explain the complexity of humans compared to simpler organisms that contain a similar number of genes. This diversity in proteins is produced by a mechanism called RNA processing or splicing, and critically, over 90% of human genes are processed in this way. So, how does RNA processing work? First, a copy of the DNA comprising a single gene is made. This molecular copy of the gene is called messenger RNA (mRNA), and this contains the information needed to make a protein. However, the mRNA molecule can be processed in multiple ways, whereby pieces are removed, and new pieces joined together, ultimately generating variations in the original genetic code such that multiple proteins can be produced from the one gene. However, when the functions of genes and proteins are tested, traditionally only a single version of the mRNA and protein is considered, therefore changes in mRNA diversity largely remain a hidden layer of cell regulation. This process seems important in cancer because 30% more mRNA processing events occur in cancer cells compared to normal cells, and in multiple cancers, including melanoma, the degree of mRNA diversity can also predict patient outcome. Despite these initial observations, how changes in mRNA diversity relates to cancer progression, particularly from primary to metastatic disease, remains unexplored.
To investigate this further, we need to understand how mRNA is processed in complex tumour ecosystems across distinct stages of progression. Thus, for this project we will apply a new and rapidly evolving sequencing technology, that provides superior resolution of mRNA processing than previously available methods, to primary and early metastatic melanoma patient samples. The advantage of this technology is that full-length mRNA molecules can be identified, which we have not been able to achieve previously. Therefore, the full degree of mRNA diversity can be detected for the first time. The main objective of this proposal is to determine the relationship between global changes in mRNA diversity and metastasis in melanoma patients, and to determine whether specific mRNA variants are predictive of melanoma progression, and if these can be targeted to prevent melanoma metastasis. Understanding this relationship may lead to new biomarkers and therapeutic approaches to stop melanoma in its tracks earlier and prevent recurrence.
Researchers:
Prof Karin Thursky, A/Prof Ashley Ng, ……Dr Damien Kee, ……et. al.
Project:
MRV are pleased to be one of the cohorts involved in the development of the National Cancer Cohort Platform. To read more about this exciting venture please click on the link:
Researchers:
Yevgeniy R. Semenov, MD, MA, A/Prof Victoria Mar, Dr Nikki Adler,
Project:
Patients with early-stage or localized cutaneous melanomas are at risk for recurrence or return of their melanoma after treatment with surgical excision. Furthermore, recurrence in early-stage melanoma accounts for majority of deaths from melanoma and is not usually detected until the disease has spread to lymph nodes or distant organs. This results in an unmet public health need to develop more advanced tools for improved stratification of high-risk melanomas tailored to individuals diagnosed with early-stage disease. We are proposing to study this with an integrated strategy focused on identifying clinical and histologic predictors for melanoma recurrence.
Researchers:
Ian Parish, Shahneen Sandhu, Lavinia Tan, Shienny Sampurno, Sara Roth, Avraham Travers, Nihali Kulkarni
Project:
Immune checkpoint blockade (ICB) targeting the cytotoxic T-lymphocyte associated protein 4 (CTLA-1) and programmed cell death protein 1 (PD-1)/PD-Ligand (L)1 axis has radically transformed the treatment landscape of cutaneous melanoma. Nonetheless, approximately 50% of patients will die from melanoma and the underlying mechanisms of primary and secondary resistance are not well understood. Cytotoxic CD8+ T cells are the dominant immune cell population involved in the elimination of malignant cells and are central effector cells that mediate the efficacy of ICB. However, CD8+ T cells are frequently unable to control tumour cells, enabling tumour progression. Increasing evidence suggests that the CD8+ T cell subsets present within the tumour draining LN, and the niches in which these cells reside, may be one of the key determinants of response to immune checkpoint blockade. The overall goal of this study is to compare the cellular subsets and niches in LNs resected from patients with stage III melanoma with different clinical outcomes, in particular, whether the T cell subsets and their associated niches present in the LN are associated with tumour recurrence or non-recurrence after ICB, and whether they better predict non-recurrence than the immune niches within the tumour. Participants with stage III melanoma who have undergone curative intent LN surgery and either received adjuvant ICB or active surveillance alone will be identified for this study. Archival tumour tissue and tumour draining LNs from the time of curative surgery and /or from subsequent tumour biopsies or resections will be collected in all cases, but participants will not be required to undergo additional tumour biopsies as part of the study.
Researchers:
Richard Rebello; Richard Tothill; Shahneen Sandhu
Project:
Cancer of unknown primary (CUP) is a metastatic cancer where clinical investigations fail to identify the primary tissue of origin (TOO). CUP patients undergo protracted diagnostic workups in a bid to resolve a cancer type diagnosis. We have shown panel sequencing can resolve ~1/3 of CUP cases (PMID: 36287571), while our more recent data shows WGS can increase diagnostic yield to ~2/3 of patients (unpublished). However, tissue availability is a barrier to testing in ~40% of cases and sourcing tissue from pathology labs extends reporting by ~18 days (SUPER study experience). Our goal is to develop a rapid liquid biopsy blood test utilising multi-omic whole genome sequencing to resolve the diagnosis of cancer of unknown primary. The test will accurately predict the primary tissue of origin of a patient’s cancer by detecting mutational and DNA methylation patterns in small amounts of DNA released from tumour cells into blood circulation.
Researchers:
Lewis Au, Paul Neeson, Andrea Di Pietro, Grant McArthur, Shahneen Sandhu
Project:
Patients with primary skin (cutaneous) melanoma have a variable clinical outcome. Whilst many patients do well, others relapse 2-5 years after surgery. Currently there are criteria for predicting who will relapse, but this is not completely accurate. Furthermore, clinical trial data has shown getting treatment with immunotherapy can increase the chance of cure in some (~10%) of patients. However, right now there is no way or tests to tell which patients will need this treatment. As such, this leads to the majority of patients potentially being exposed to treatment they don’t need along with the associated side effects to treatment. To improve this situation, a diagnostic test that can predict which patients are both at high risk of relapse and will benefit from immunotherapy, is critically needed.
In this project we will address this issue. We already have preliminary data suggesting that analysing a diagnostic test using tumour slides from the surgically removed melanoma which is readily available, may be possible. However, to do this, we will need to collaborate with expertis in digital pathology and use artificial intelligence.
We propose to use our available resource in MRV with our repository of tumour slides to collaborate with ARTERA AI, a USA based company who already have a track-record developing digital pathology assays in cancer. Their first assay is well on it’s way to become a diagnostic test to predict treatment effects if prostate cancer – and we plan to work together in a similar fashion to improve the outcomes of patients with early stage melanoma.
This is important because it will enable melanoma oncologists to make decisions about patient treatment, and also provide patients with a greater degree of certainty about their future.
Researchers:
Dr Noor E Karishma Shaik, Prof Marimuthu Palaniswami, Dr Eric Hoefgen, Dr Nandakishor Desai
Researchers:
Dr Lorey Smith, Dr Ivan Topisirovic, Dr Lynne Postovit
Project:
Melanoma is an aggressive form of skin cancer that is still incurable once it spreads (metastasizes). As part of the metastatic process, cells undergo various molecular changes, which allow them to invade surrounding tissues, survive in circulation and grow in their new surroundings. The ability of cancer cells to adapt to these challenges includes changes in how they convert fuel (e.g. nutrients) to energy. Through constant remodeling of their gene expression and metabolic programs, melanoma cells develop plasticity, whereby they can attain different phenotypes which allows them to survive under condition where oxygen and nutrients are limiting, invade surrounding tissues and spread around the body. Herein, we aim to improve the understanding of the mechanisms of adaptation and plasticity which are pertinent to dissemination of melanoma. Our preliminary studies identified secreted frizzled related 1 (SFRP1) as a major factor which modulates metabolism while contributing to melanoma plasticity. We propose to follow up on these preliminary findings and identify SFRP1-dependent mechanisms used by melanoma cells to escape immune surveillance, maintain energy balance and generate building blocks in the context of plasticity and metastatic spread. These studies are anticipated to establish better understanding of melanoma growth and metastatis as well as their responses to immunotherapies.
Researchers:
Paul Neeson, Shahneen Sandhu, George Au Yeung, David Gyorki, Liz Christie, Lewis Au
Project:
Predicting poor outcome patients: Patients with primary skin (cutaneous) melanoma have a variable clinical outcome. Whilst many patients do well, others relapse 2-5 years after surgery. Currently there are criteria for predicting who will relapse, but this is not completely accurate. In this project we will address this issue. We will perform a deep analysis of primary cutaneous melanoma from a large number of patients and compare our data for patients who later developed disease or remain disease free. This information will then be used to develop a set of results (biomarkers) which will better predict patient clinical outcome. This is important because it will enable melanoma oncologists to make decisions about patient treatment, and also provide patients with a greater degree of certainty about their future.
Researchers:
Paul Neeson, Shahneen Sandhu, George Au Yeung, David Gyorki, Grant McArthur
Project:
Why tissue resident T cells in melanoma matter: Melanoma is a disease which induces an immune response. The immune response is generated over a long period of time as the melanoma tumour develops. As a result melanoma reactive immune cells (T cells) are present within (1) the tumour itself (tissue resident T cells), (2) in local or distant lymph nodes (memory T cells) or (3) moving between these two sites in the blood. The tissue resident T cells contain the most important and effective melanoma-controlling cells. Increased numbers of tissue resident T cells are associated with improved clinical outcome for patients with metastatic disease. In this project, we will explore whether increased resident memory T cells can predict a good outcome for patients with melanoma of the skin at a very early stage. This is important because it will enable melanoma oncologists to make decisions about patient treatment, and also provide patients with a greater degree of certainty about their future.
Researchers:
Dr Julia Lai-Kwon, Prof Michael Jessord, Mr Mees Egeler, Prof Lonneke van de Polle-Franse
Project:
Adjuvant (ie. following surgery) immunotherapy treatments such as pembrolizumab and nivolumab reduce the risk of melanoma recurring in people with resected stage III and IV melanoma. More people are living longer following treatment for resected stage III and IV melanoma and there is therefore growing interest in assessing the impact of these treatments on all aspects of their quality of life (QOL). This includes the impact on symptoms caused by the drug treatment, how well they function day-to-day, as well as their overall QOL. Understanding this can be helpful to others who are deciding whether or not to have adjuvant immunotherapy.
Currently, there is no data regarding the impact of adjuvant immunotherapy on QOL from people who have not participated in a clinical trial. People who participate in clinical trials are often healthier than those who do not participate in clinical trials, and therefore this is not representative of the overall population who receive these treatments. We also do not know whether the impact on QOL differs between countries, as we know that cultural background can influence people’s perceptions of their QOL.
This study will therefore involve people with resected stage III/IV melanoma who have received adjuvant immunotherapy in Australia and the Netherlands. It will examine the impact of treatment on their symptoms, level of day-to-day function, and overall QOL as measured by a standardised survey called the EORTC QLQ-C30. This will be used to help people choose whether or not to have adjuvant immunotherapy and identify areas where there is need for more supportive care services.
Researchers:
Dr Matilda Anderson, Dr Hayden Snow, A/Prof David Gyorki et al
Project:
This is an international, multi-centre retrospective study aiming to compare treatment options for melanoma patients presenting with local metastases (called ‘in-transit’ or ‘satellite’) which are not suitable for surgical treatment. Approximately 5-10% of patients with high-risk melanoma will develop these metastases [1]. It is a form of tumour which spreads within the skin and subcutaneous lymphatic channels between the primary melanoma site and the local lymph nodes.
Surgical excision is the primary treatment of these metastases, however for some patients the disease is too extensive or unsuitable for surgery. There are then several treatment options available, with the aim to reduce this local disease as well as the risk of distant metastases. These treatments include local treatments (directly on the tumour or limb) and systemic treatments (immune therapy). There are no direct comparisons between the treatments to assist and guide treatment recommendations.
This study aims to address this information gap, by comparing outcomes of patients treated with these different modalities. The primary aim is to assess local tumour response to treatment, with secondary aims looking at overall patient outcomes such as time to future further local disease, time to distant metastases, and patient survival. Data from over 20 different international sites will be collected, including the Peter Maccallum Institute in Melbourne, Victoria.
Researchers:
Dr Roslyn Wallace, Dr Aparna Rao and Prof Grant McArthur
Project:
Melanoma is the third most common cancer in Australia.1 Historically, unresectable melanoma had a very poor prognosis with little response to chemotherapy.2,3 Clinical outcomes have greatly improved with the advent of immunotherapy.4 Unfortunately, most patients either have no initial response to treatment or develop resistance4 as such there is a need to develop non-invasive biomarkers which predict response to immunotherapy to avoid subjecting patients to a futile and potentially toxic treatment.
Elevated Lactate dehydrogenase (LDH) is associated with a poor prognosis in melanoma.5 An elevated LDH at diagnosis is also predictive of a poorer overall survival in patients receiving immunotherapy.6 It is considered to be a surrogate for tumour volume,6 however there are a small number of patients with discordant LDH levels and tumour volume i.e. patients with high LDH and low tumour volume and vice versa.
This project aims to determine the utility of LDH as a predictive biomarker for response to immunotherapy, independent of its association with tumour volume. We will identify a cohort of patients in whom a discordance between serum LDH and tumour volume is observed and identify groups of matched controls for comparison. Within the cohorts we will correlate serum LDH, tumour volume with other biological features specifically those associated with tumour metabolism. We will assess gene expression to determine differences in metabolic or other pathways that may underpin discordance between serum LDH and tumour volume.
1.AIHW:
2.Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158-66, 2000
3.Chapman PB, Einhorn LH, Meyers ML, et al: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745-51, 1999
4.Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 381:1535-1546, 2019
5.Manola J, Atkins M, Ibrahim J, et al: Prognostic factors in metastatic melanoma: a pooled analysis of Eastern Cooperative Oncology Group trials. J Clin Oncol 18:3782-93, 2000
6. Wagner NB, Forschner A, Leiter U, et al: S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies. Br J Cancer 119:339-346, 2018
Researchers:
Dr Prachi Bhave, Prof Grant McArthur and Prof Tony Papenfuss
Project:
This project will explore the characteristics of melanomas that behave in an expected fashion. This includes two groups:
1. Very thin melanomas that return within 2 years after removal, as normally such thin melanomas are cured with surgery and do not come back.
2. Very thick melanomas that do not return after 5 or more years of follow up, as normally such thick melanomas would be expected to return and/or spread within a few years of surgical removal.
Researchers:
Dr Jonathan McCafferty and A/Prof David Gyorki
Project:
Most melanoma studies focus on survival related outcomes. Patients with positive sentinel lymph nodes are known to be at a higher risk of melanoma specific mortality. We hope to better characterise the recurrence pattern of patients with sentinel lymph node positive disease, as well as the mechanism of detection of recurrence.
There is no global consensus for the surveillance of patients with melanoma and positive sentinel lymph nodes. At the Peter MacCallum Cancer Centre, we utilise PET-CT surveillance as part of our protocol for patients with positive sentinel lymph nodes. We hope to evaluate the utility of PETCT surveillance in these patients.
Researchers:
Prof Maarten Ijzerman, Dr Fanny Franchini; Dr Jennifer Soon
Project:
PRIMCAT is a Commonwealth funded multi-institutional research program that will support the decision-making processes of Australia’s Health Technology Assessment (HTA) agencies. It will provide evidence-based, internationally validated forward estimates of the number of Australian patients who may benefit from new cancer treatments and the associated population health economic impacts for the health system. Read More
Researchers:
Dr Aparna Rao, A/Prof David Gyorki, Prof Grant McArthur, Prof ralph DeBerardinis, Dr Jennifer Gill, Mrs Alison Button-Sloan
Project:
Australia has the highest incidence of melanoma globally. Although newer therapies, such as immunotherapies and targeted therapies, have dramatically improved outcomes, we have limited understanding why some patients relapse or do not respond to therapy. Understanding fuels that tumours use to derive energy (metabolism) could potentially answer such questions. In this initiative we will use novel techniques to characterise melanoma metabolism in living tumours.
These ground–?breaking techniques have only been developed and refined in recent years and we now have an exciting opportunity to gain insights into tumour metabolism in a manner that was impossible in the past. The technique we will use involves assessing characteristics of the metabolism of a tumour from a standard biopsy sample (using a method known as metabolomics), to get a detailed view of how melanomas use these fuels to aid their growth. Ultimately, we aim to apply the knowledge gained from these studies to predict outcomes and develop novel therapies for patients with melanoma.
Researchers:
Dr Meni Brahka, A/Prof David Gyorki
Project:
In clinical practice, a small subset of patients diagnosed with primary cutaneous malignant melanoma have an unusual clinical course, with rapidly progressive disease resulting in early death. There are various well-described risk factors for poor prognosis in melanoma patients, but there is no well documented prediction model that can be used to identify the patients who will experience rapidly progressive disease.
Based on the MRV database, this study was designed to identify indicators and risk factors for the development of rapidly progressive melanoma, allowing clinicians to recognize high-risk patients at the time of diagnosis and benefit clinical management and improve decision making.
Researchers:
Dr Matilda Anderson, Dr Hayden Snow, A/Pro David Gyorki
Project:
Immune engagement occurs when the immune system recognizes a tumour and interacts with it. The extent and quality of this engagement can dictate the response to certain treatments, especially those aiming to enhance the patient’s immune system (immunotherapy). This project will use a non-invasive novel technology to measure the extent of immune engagement using a drop of blood in melanoma patients undergoing immunotherapy to predict therapy success.
Researchers:
Dr Charlie Wang, Tori Mar, Fanny Francini, Marliese Alexander, Andrew Haydon, Mark Shackleton
Project:
A project is underway using data from the MRV and Pharmaceutical Benefits’ Scheme database to see if cholesterol-lowering medications called statins are beneficial in patients with a high-risk melanoma. The study will also examine the effect of statins on newer treatments such as immunotherapy. Results of this study may guide clinicians on how to optimise long-term melanoma care. A project is underway using data from the MRV and Pharmaceutical Benefits’ Scheme database to see if cholesterol-lowering medications called statins are beneficial in patients with a high-risk melanoma. The study will also examine the effect of statins on newer treatments such as immunotherapy. Results of this study may guide clinicians on how to optimise long-term melanoma care.
Researchers:
Dr Dale Jobson, Professors Chris McCormack, Michael Henderson and Constantine Tam
Project:
Melanoma is diagnosed in approximately 232,000 patients worldwide annually with over 55,500 death. Immunosuppressed people have poor melanoma outcomes, in particular, those with underlying chronic lymphocytic leukemia (a common blood cancer). With the help of Melanoma Research Victoria we hope to find out why patients with blood cancer do so poorly so we can better help them.
Jobson D, McCormack CJ, Mar V, Tam C, Henderson MA. Impact of chronic lymphocytic leukaemia on melanoma outcomes: A retrospective case-control study. Br J Haematol. 2022;00:1– 6. ht t ps://doi.org /10.1111/ bjh.18090
Researchers:
Dr Edward Stanley, A/Prof Victoria Mar, A/Prof David Gyorki
Project:
The aim of the study is to investigate factors contributing to regional recurrence or metastasis of malignant melanoma following excision of cutaneous melanoma with a negative sentinel lymph node biopsy (SLNB).
Furthermore, there has been an increased use of partial biopsies in the diagnosis of cutaneous melanoma due to a belief that this technique will minimise the number of missed malignancies on sentinel lymph node biopsies. The current study will focus on patients who have undergone sentinel lymph node biopsies to assess whether the type of biopsy used on a primary melanoma will affect the likelihood of having a false negative sentinel lymph node biopsy. The project will also assess other factors and whether these will increase the risk of a missed malignancy on sentinel biopsy, thus increasing the risk of undiagnosed and untreated regional recurrence or distant metastases.
Researchers:
Ms Sonia Mailer, Dr Joanne Britto, Prof Grant McArthur
Project:
Using the hypothesis: the current structure of consumer engagement in clinical research limits consumer-led research we interrogated the Melanoma Research Victoria model. We undertook an audit of all aspects of MRV, and in particular MRV consumer activities, over a ten year period. A mixed methods survey was then used to ask key stakeholder for their perspectives regarding the model and their thoughts on why there was minimal evidence of consumer-led research in MRV.
Researchers:
Ms Isobel Leece, Mark Shackleton
Project:
The aptly named Natural Killer (NK) cells are types of immune cell which display limited anti-cancer activity in primary melanomas, but have high potential for controlling metastatic spread, based on laboratory studies to date. Normally, these NK cells are found patrolling the blood, liver and in sites of inflammation. Some NK cell subtypes are in lymph nodes, but these have not been thought to possess great killing activity, rather to function in immune response regulation. While initial investigations have shown that melanoma invasion of lymph nodes can result in an influx of true killer NK cells, the prognostic significance of NK cells in lymph nodes is not known.
By using the Opal Immunohistochemistry platform, we plan to study interactions between NK cells and melanoma deposits in lymph nodes. This technology platform allows us to study 7 different immune and melanoma markers on one slide to understand complex relationships between immune and melanoma cells. This higher resolution understanding of melanoma metastases in lymph nodes, combined with clinical annotations, will help us determine whether NK infiltration in early lymph node metastasis is associated with disease relapse after surgery. In this case, the presence of NK cells in lymph node metastases might be used to determine further treatment to reduce risk of melanoma recurrence.
Researchers:
Mr Josh Bouwhuis, A/Prof David Gyorki
Project:
Advanced stage melanoma is historically associated with poor outcomes despite treatment with the mainstays of cancer therapy i.e. surgery, radiation and chemotherapy. The recent development of immune checkpoint inhibitors (ICI), has improved these outcomes drastically both in patients with metastatic disease as well as more recently in the adjuvant setting for melanoma and many other cancers. Despite these rapid advancements, a large proportion of patients either do not respond or will develop resistance to ICI over time. Consequently, there has been great interest in discovering factors that can predict the likelihood of ICI response. Disruption of the gut microbiome i.e. dysbiosis, has been increasingly linked to reducing the function of the host immune system, highlighting a potential mechanism that may influence patient responses to ICIs.
Antibiotics (ABX) are a widely known cause of dysbiosis. Post-operative wound infection is a recognised complication of lymphadenectomy requiring the use of prolonged antibiotics. The majority of recent studies have shown that ABX usage shortly before or after beginning ICI therapy for metastatic disease is associated with poorer outcomes in terms of progression free survival and overall survival. These results are somewhat controversial as there are many possible confounding influences on both the microbiome and immune system in general and have yet to make any impact on routine clinical practice for surgeons and oncologists in Australia. There have not been any studies looking at antibiotics use in patients receiving adjuvant immunotherapy. This proposed retrospective data analysis will hopefully provide further insight on this topic and add to the growing research base in this field.
Researchers:
Ms Karen Trapani, A/Prof Anna Boltong, Dr Fanny Franchini, Prof Maarten Ijzerman
Project:
Optimal Cancer Care Pathways (OCPs), a government policy initiative, are national guides to promote best practice cancer care for specific cancer types. They aim to improve patient outcomes by promoting quality cancer care and ensuring that all people diagnosed with cancer receive the best care, regardless of where they live or receive cancer treatment.
The aim of this project is to analyse the diagnostic interval (time from initial presentation to diagnosis), measuring alignment with the recommendations of the Melanoma OCP and investigating associations between alignment and patient outcomes.
Researchers:
Dr Jennifer Soon, Prof Grant McArthur
Project:
An exploratory review of the MRV database to identify any emerging trends or patterns in clinicopathological features and/or outcomes of melanoma patients who have comorbid immunosuppressive conditions.
Researchers:
Prof Mark Shackleton, Nathan Hall, Dr Gregory Gaughran, GMDx Group
Project:
Melanoma is an aggressive skin cancer that can have poor outcomes. It is the fourth most common cancer diagnosed in Australia, with ~14,000 new cases per year (the highest incidence in the world). Unfortunately, melanomas are often undetected in the very early stages and some are not detected until they have spread from the skin to other body sites. In these cases, treatments such as immunotherapy are often recommended.
Immunotherapy is a new type of cancer treatment which stimulates the body’s immune system to kill cancer cells. These drugs typically benefit ~50% of patients, and can be successful when other therapies fail. Despite these benefits, immunotherapy infrequently causes severe and/or permanent side effects. In this light, it is very important to be able to predict which patients will respond to immunotherapy, although our ability to do this is currently limited.
Our aim is to develop a genetic test of a patient’s melanoma to determine which patients will respond to immunotherapy. This will enable a more personalised approach to treatment, with immunotherapy only prescribed in patients predicted to respond. Our preliminary work demonstrates our ability to predict patient outcomes using advanced machine learning techniques, and our goal in this project is to refine these methods to increase the accuracy of our predictions. The best method to increase accuracy of predictions is to train machine learning models on large, well-curated datasets, such as are available through Melanoma Research Victoria
This project is a collaboration between Mark Shackleton (Director of Oncology, The Alfred Hospital) and the GMDx Group, a biotechnology company that has patented a method to predict immunotherapy response from easily-obtained genetic information about a patient’s cancer. We plan to undertake genetic sequencing of melanomas from 250 patients that either did or didn’t respond to immunotherapy.
We expect that by bringing together the GMDx Group’s patented therapy response prediction machine learning methods and data from the MRV cohort, we will develop a test to predict accurately a patient’s response to immunotherapy.
Researchers:
Dr Alfredo DeFariaFreitas, Dr David Gyorki, Prof Michael Henderson
Project:
Retrospective cohort study using simple perioperative biomarkers available from a full-blood examination (FBE) to predict poor outcome after cancer surgery.
Researchers:
Dr Peter Lau, Dr Arian Lasocki, Dr Lorey Smith, A/Prof Paul Neeson, Dr Ismael Vergara, Dr David Gyorki, Professor Mark Shackleton, A/Prof Shahneen Sandhu, Dr David Kok, Professor Grant McArthur
Project:
Melanoma brain metastases are a common problem with approximately 40% of patients developing brain metastases during treatment with systemic therapies. Modern systemic therapies including targeted therapies (BRAF-MEK inhibitors) and combination immunotherapies (ipilimumabnivolumab) both display high response rates of approximately 55-60% in patients with brain metastases. Despite this, a high proportion of patients treated with targeted therapies eventually relapse and require a switch to combination immunotherapy.
PBMCs is a research project that is attempting to better understand how BRAF mutant melanoma brain metastases continue to grow following treatment with targeted therapy. We will utilise a range of sequencing technologies to identify RNA and DNA changes of brain metastases together with sophisticated imaging techniques to identify immune cells of interest. We
hope to discover the mechanisms of resistance to BRAF/MEK inhibitor treatment specifically in brain metastases, and how this effects the immune system and response to immunotherapy. This knowledge will provide critical information on the optimal sequence of targeted versus immune therapies for
melanoma patients with brain metastases, and potentially identify new therapeutic targets for melanoma.
Researchers:
Dr Malaka Ameratunga, Prof Mark Shackleton, Prof Catriona Mclean
Project:
Melanomas are characterised by excess production of melanin, a brown-black pigment. As melanomas progress, they sometimes lose their characteristic pigment and become pale. Preliminary work in our laboratory has established the gene AXL as being a critical component of the transition to this loss of pigment state and there are drugs targeting AXL that are undergoing development. AXL has also been linked to therapy resistance. We wish to confirm, with patient samples, that AXL is in fact linked to depigmentation and therapy resistance, which may inform clinical studies in the future to test this exciting concept.
Researchers:
Dr Jennifer Downs, Dr David Gyorki
Project:
Management of melanoma lymph node disease has changed with access to new drugs and publication of new evidence that has changes the way lymph node disease is managed all over the world. This study will collaborate with multiple international centres to assess how patients are responding to new management practices of their lymph node disease.
Researchers:
Dr Matilda Anderson, Dr Hayden Snow, A/Pro David Gyorki
Project:
This is an international, multi-centre retrospective study aiming to compare treatment options for melanoma patients presenting with local metastases (called ‘in-transit’ or ‘satellite’) which are not suitable for surgical treatment. Approximately 5-10% of patients with high-risk melanoma will develop these metastases [1]. It is a form of tumour which spreads within the skin and subcutaneous lymphatic channels between the primary melanoma site and the local lymph nodes.
Surgical excision is the primary treatment of these metastases, however for some patients the disease is too extensive or unsuitable for surgery. There are then several treatment options available, with the aim to reduce this local disease as well as the risk of distant metastases. These treatments include local treatments (directly on the tumour or limb) and systemic treatments (immune therapy). There are no direct comparisons between the treatments to assist and guide treatment recommendations.
This study aims to address this information gap, by comparing outcomes of patients treated with these different modalities. The primary aim is to assess local tumour response to treatment, with secondary aims looking at overall patient outcomes such as time to future further local disease, time to distant metastases, and patient survival. Data from over 20 different international sites will be collected, including the Peter Maccallum Institute in Melbourne, Victoria.
