Making Cancer Cells lose a game of hide-and-seek

Making Cancer Cells lose a game of hide-and-seek.

We celebrated St. Patrick’s Day with a pot of research gold! As the world celebrated Ireland’s national holiday with a pint of Guinness in hand, Dr Conor Kearney, head of our Molecular Immunology Lab delivers a scientific breakthrough that’s as thrilling as a jig on Temple Bar. Born under the sunny skies of Australia but raised on the Emerald Isle, Dr  Kearney undertook his PhD in Trinity College, Dublin. However, he felt the irresistible pull of his antipodes, drawing him back to Australia after spending most of his life in Ireland to continue his research career.

In his latest publication in Cell Reports, Dr Kearney and his team unveil ground-breaking findings that significantly contribute to our fight against cancer.

“We have conducted a world first epigenetic-targeted CRISPR screen to identify the ways by which cancer cells hide from our immune system,” said Dr Kearney in his unmistakable Irish lilt.

“We identified a protein that can shield cancer cells from being attacked by immune cells. More importantly, we demonstrate that by stopping the function of this protein with a drug which is currently in clinical trials, we now make these cancer cells more visible to attack by our immune cells.”

Just as wearing green on St. Patrick’s Day is supposed to make you invisible to leprechauns to avoid their cheeky pinch, Dr Kearney’s study suggests a way to disrobe cancer cells of anything green to expose them to our immune system.

A graphical extract from the report

“This is potentially a game-changer in the world of immunotherapy, especially for patients battling solid cancers where responses are often elusive.”

As St. Patrick’s Day festivities kick into high gear, Dr Kearney’s research serves as a reminder of the resilience and ingenuity that define the Irish spirit. With a nod to his roots, Dr  Kearney continues to lead the charge in the quest for a cancer-free future on the other side of the rainbow.


ONJCRI Rare Cancer Clinical trial bringing treatment to regional Australians

ONJCRI MoST CIRCUIT Clinical Trial Enrols 240 Rare Cancer Patients

The Olivia Newton-John Cancer Research Institute (ONJCRI) announced it has successfully enrolled 240 rare cancer patients into its MoST CIRCUIT clinical trial in rare cancers. This trial is delivering immunotherapy treatment to urban, regional and rural patients with currently untreatable rare cancers. Leveraging the tele trial networks in regional Victoria and QLD, and support from major hospitals in NSW, WA, TAS, SA, VIC and Auckland, ONJCRI is delivering potentially lifesaving cancer treatments to rare cancer patients who would otherwise have no access.

Patients with rare cancers, each individually with an incidence of <2 in 100,000, represent approximately 20% of all cancer diagnoses and have very limited treatment options available. Subsequently, they have a lower overall survival compared to patients with more common malignancies, contribute to 50% of the global cancer death rate, and represent a significant unmet medical need.

Almost a third of Australians live in rural, regional and remote areas, and are frequently unable to access clinical trials.  The limited availability of clinical trials in regional areas often means patients must travel huge distances to access treatment including interstate.

Dr Oliver Klein, an immunologist and lead clinician for the trial reiterated:

 “Rare cancers are difficult to study and treat due to their infrequent nature. Combination immunotherapy can be incredibly effective in patients with rare cancers, and being able to identify factors, such as the microbiome, that are predictive of an effective response will be invaluable in making this treatment available to more patients.”

Through the support of the Minderoo foundation, Bristol Myers-Squibb and OMICO, this study has enabled patients with rare neuroendocrine, biliary tract, gynaecological and mismatch repair protein deficient (MSI-H) cancers to access immunotherapy and contribute to national data initiatives that evaluate and improve rare-cancer patient outcomes.


Professor Matthias Ernst’s team receives Cancer Council Victoria funding for research into pancreatic cancer

Professor Matthias Ernst’s team receives Cancer Council Victoria funding for research into pancreatic cancer

Congratulations to Professor Matthias Ernst, Head of the Tumour Environment and Immunology Program at the Olivia Newton-John Cancer Research Institute and Dr Moritz Eissmann, Head of the Cytokine and Cancer Signalling Group at ONJCRI, who are the recipients of a Cancer Council Victoria 2024 Grants-in-Aid. The Cancer Council Victoria’s Grants-in-Aid program funds high-quality research projects into the treatment, causes, detection and prevention of all cancers.

Professor Ernst and Dr Eissmann, in collaboration with A/Prof Marina Pajic from the Garvan Institute, and Prof Mehrdad Nikfarjam from University of Melbourne received funding for their project ‘Identification of therapeutic vulnerabilities that promote metastatic spread of pancreatic cancer’. The Grants-in-Aid program supports research for 1 to 3 years, with applicants undergoing a rigorous peer-review process.

Professor Ernst said, “the grant supports our work which seeks to determine mechanisms of how pancreatic cancer adapts over time to develop resistance and avoid detection by our immune system. By understanding the underlying molecular mechanisms, which are likely to involve dialogue between cancer cells and the normal cells surrounding them, we will be able to identify new drug targets. Such drugs will open possibilities to make pancreatic cancer cells more vulnerable to immunotherapy.”

Pancreatic cancer ranks as the sixth most prevalent cancer, yet its survival rate remains disheartening, with fewer than 1 in 10 patients surviving 5 years post-diagnosis. Despite significant strides in treating other forms of cancer, progress in controlling pancreatic cancer has been notably limited. This is particularly true for immunotherapy, where most pancreatic cancer cases either do not respond to immunotherapy or rapidly develop resistance, unlike in other cancers such as melanoma.

Building on our observations that cancer cells are made up of different clones, it is important to identify which of these clones are responsible for a cancer to become resistant to treatment so that these clones can be eliminated early.

“Our CCV grant will explore how pancreatic cancers evade immune cell attack at a molecular level. These mechanisms may also be used by other cancer cells, making our findings relevant beyond pancreatic cancer.” Dr Eissmann said.


Dr Lisa Mielke announced among Victoria's most outstanding mid-career cancer researchers

Dr Lisa Mielke announced among Victoria's most outstanding mid-career cancer researchers.

The Olivia Newton-John Cancer Research Institute is thrilled to announce that Dr. Lisa Mielke has been honoured with the prestigious 2023-2024 Monash Partners Comprehensive Cancer Consortium (MPCCC) Mid-Career Award for Outstanding Cancer Research. This accolade is a testament to Dr. Mielke’s outstanding contributions to cancer research, particularly her work in cancer immunology, which focuses on enhancing the anti-tumour response of a relatively understudied immune cell type in the fight against bowel cancer.

Dr. Mielke leads the Mucosal Immunity and Cancer Laboratory at ONJCRI, where her research delves into the intricate relationship between immune cells and cancer, with a particular focus on bowel cancer. Her work has unveiled the critical role of gamma delta (γδ) T cells in preventing the development and progression of cancer within the large bowel. Dr. Mielke and her team discovered that a molecule called TCF-1, suppresses the natural activity of γδ T cells, which are crucial for combating bowel cancer. In pre-clinical studies they could show that when TCF-1 was deleted in these immune cells, the anti-tumour immunity significantly increased, resulting in a reduction in tumour burden.

This insight may open new avenues for improving immunotherapy treatments for bowel cancer, by targeting TCF-1, thereby enhancing the anti-tumour response. The significance of Dr. Mielke’s research extends beyond the scientific community.

By focusing on anticancer therapies that aim to minimise treatment toxicity, her work aligns with ONJCRI’s mission to improve quality of life for cancer patients. Her achievements exemplify the institute’s commitment to pioneering research that offers hope for more effective cancer treatments. Chief Executive Officer of ONJCRI, Professor Marco Herold, stated “there is no doubt, Lisa is destined to be a world leader in the field of cancer immunology.  Her collaborative approach to research, enthusiasm, and talent to teach the next generation of scientists will lead to many exciting discoveries benefitting cancer patients. We are immensely proud of Lisa, and we look forward to seeing the impact of her work in the future.”

By supporting research like Dr. Mielke’s, we can all contribute to the fight against cancer, entering a new era of more effective and compassionate care.


BioNTech Founders visit the Olivia Newton-John Cancer Research Institute

BioNTech Founders visit the Olivia Newton-John Cancer Research Institute, marking new innovative possibilities for combatting cancer.

La Trobe University was recently announced as the new home for the manufacturing of investigational mRNA therapies, for the global biotechnology company BioNTech, in a multi-year strategic partnership with the Victorian State Government. The facility, to be located at La Trobe University’s Bundoora campus, is based on the Company’s high-tech, digitally enabled modular manufacturing units, the BioNTainers.

The facility will not only produce mRNA therapies but also drive research into mRNA-based vaccine and therapy development, with a focus on addressing cancers with high unmet clinical need. BioNTech, renowned for its ground-breaking work alongside its partner, Pfizer in creating the world’s first approved COVID-19 vaccine, Comirnaty® (BNT162b2), stands as a global leader in next generation immunotherapy. The company is at the forefront of pioneering novel therapies for cancer, and other serious diseases.

In a significant event held in October 2023, BioNTech co-founders Professor Uğur Şahin, Chief Executive Officer, and Professor Özlem Türeci, Chief Medical Officer, visited the Olivia Newton-John Cancer Research Institute, La Trobe University’s School of Cancer Medicine. The visit preceded a special ceremony in Melbourne, where Professors Şahin and Türeci, together with Professor Sharon Lewin AO (Director, Doherty Institute) were presented with an Honorary Doctor of Science by La Trobe University Chancellor, the Hon John Brumby AO, who is also the past inaugural Chair of the ONJCRI.

Accompanied by their team, the BioNTech founders were joined by members of La Trobe University’s Senior Executive Group and staff, as well as representatives from mRNA Victoria, the ONJCRI Board of Directors and Austin Health.

The day commenced with an insightful tour of the ONJCRI facilities, guided by Institute staff and students, and concluded with a presentation by Professor Marco Herold, Chief Executive Officer of the Olivia Newton-John Cancer Research Institute and Head of the La Trobe University School of Cancer Medicine.

Expressing enthusiasm about the partnership, Professor Herold said;

“We are excited by this strategic partnership between BioNTech and La Trobe University to explore mRNA technology innovations for the treatment of currently incurable cancers. As an Institute with key strengths in immunotherapy, we are eager to embark on collaborative projects with BioNTech to harness the power of mRNA technology for effective cancer treatment”.

Image source: La Trobe University


Discovering new approaches to prevent metastasis of breast, colon and liver cancers

Discovering new approaches to prevent metastasis of breast, colon and liver cancers

Supervisors: Dr Bhupinder Pal, Prof John Mariadason and A/Prof Naiyang Fu (WEHI)

Laboratories: Cancer Single Cell Genomics Laboratory

Colorectal cancer claims the lives of over 5000 Australian’s each year.  Chemotherapy and radiation therapy are routinely used to treat these tumours, however not all patients respond to these treatments. This PhD project will seek to develop new ways to increase the effectiveness of chemotherapy and radiation therapy by testing new therapeutics in cell line, organoid and mouse models of this disease, and investigating their underlying mechanisms of action. It also involves the use of genetic screens such as CRISPR/Cas9 to discover new drivers of drug resistance.

The project will provide the candidate with extensive knowledge of cancer biology, and the transcriptional and signaling pathways which drive the response to drug treatment. The candidate will also gain expertise into the use of cutting-edge discovery tools such as molecular profiling, CRISPR screening and drug screening, and the use of mouse models and clinical samples to address critical questions that can improve outcomes for cancer patients.


Enhancing the efficacy of chemotherapy and radiation therapy in colorectal cancer

Enhancing the efficacy of chemotherapy and radiation therapy in colorectal cancer.

Supervisors: Prof John Mariadason, Dr Ian Luk, Dr Fiona Chionh

Laboratories: Oncogenic Transcription Laboratory

Colorectal cancer claims the lives of over 5000 Australian’s each year.  Chemotherapy and radiation therapy are routinely used to treat these tumours, however not all patients respond to these treatments. This PhD project will seek to develop new ways to increase the effectiveness of chemotherapy and radiation therapy by testing new therapeutics in cell line, organoid and mouse models of this disease, and investigating their underlying mechanisms of action. It also involves the use of genetic screens such as CRISPR/Cas9 to discover new drivers of drug resistance.

The project will provide the candidate with extensive knowledge of cancer biology, and the transcriptional and signaling pathways which drive the response to drug treatment. The candidate will also gain expertise into the use of cutting-edge discovery tools such as molecular profiling, CRISPR screening and drug screening, and the use of mouse models and clinical samples to address critical questions that can improve outcomes for cancer patients.


Tuft Cells in the GI Cancer Microbiome: Unraveling their Role in Microbial Regulation

Tuft Cells in the GI Cancer Microbiome: Unraveling their Role in Microbial Regulation

Supervisors: A/Prof Michael Buchert, Prof Matthias Ernst

Laboratories: Cancer and Inflammation Laboratory

Until recently, it was common to think that tumours are simply masses of a patient’s own cells that malfunction and grow uncontrollably when they, in fact, are communities of many different cell types. New research has now shown that tumours also play hosts to a collection of other life-forms entirely – microorganisms such as bacteria and fungi, some of which thrive in the environment around the tumour while others live inside the tumour cells themselves. Until recently it was unknown what roles these microbes play in tumours, however novel findings show that they can either assist or oppose tumour development and progression. For example, bacteria can protect the tumours by inactivating chemotherapy drugs or altering the ability of the immune system to target and destroy tumour cells, while other bacteria protect the body from tumour growth by detoxifying carcinogens or reducing levels of harmful reactive oxygen molecules that can damage DNA. This area of cancer microbiology is an emerging and exciting topic of research and promises to lead to new approaches for treating and preventing cancers.

Tuft cells (TCs) are a rare chemosensory epithelial cell type in the gastrointestinal (GI) tract and sole source of epithelial interleukin (IL) 25. TCs have an important function as immune sentinels in the epithelium that relay danger signals to the mucosa-resident immune cells in order to maintain a healthy tissue. Recently, TCs were shown to detect the presence of certain microbial metabolites and to induce the expression of IL13 in cells of the innate immune system which in turn altered the expression profile of antimicrobial peptides (AMPs) in epithelial cell types such as Paneth and goblet cells which led to changes in the composition of the mucosal microbiota. Moreover, treatment of mice with IL25 alone was sufficient to induce similar changes to the microbiota in the absence of microbial metabolites. Thus, TCs can sense and regulate the makeup of the resident microbial communities.

The aim of this PhD project is to investigate whether TCs inside or outside of the tumour tissue are involved in the regulation of the tumour-associated microbiota. We will use preclinical GI tumour models where we can specifically ablate TCs either in the tumour or in the unaffected surrounding healthy tissue and determine the abundance and composition of microbial communities by 16S RNA sequencing.  We will further complement these experiments by pharmacologically blocking the activity of IL25 and IL13 in vivo. Lastly, we will determine the impact of both genetic and pharmacologic approaches on the ability of the host immune system or chemotherapy treatments to limit tumour growth.

The project will provide the candidate with the opportunity to work in cancer microbiology, an emergent and exciting new area of cancer research. Basic training in immunology/microbiology or cancer biology (Honours or Masters minimum) will be required.

Techniques involved:

  • Flow cytometry
  • Immunofluorescent microscopy
  • 16S RNA sequencing

Recommended reading:

  1. The microbiome and human cancer. Science. 2021 Mar 26;371(6536)
  2. Tuft cells mediate commensal remodeling of the small intestinal antimicrobial landscape. Proc Natl Acad Sci U S A. 2023 Jun 6;120(23)
  3. Cross talk between Paneth and tuft cells drives dysbiosis and inflammation in the gut mucosa. Proc Natl Acad Sci U S A. 2023 Jun 20;120(25)


Choosing the right T cell for CAR therapy approaches

Choosing the right T cell for CAR therapy approaches

Supervisors: A/Prof Andreas Behren, A/Prof Paul Beavis (PMCC), Dr Fern Koay (PDI)

Laboratories: Tumour Immunology Laboratory

Chimeric Antigen Receptor (CAR) T cells have shown clinical success in hematological cancers with multiple therapies approved around the world. However, no similar success can be reported for the treatment of human solid tumours. Multiple strategies have been suggested to overcome the issues related to treatment failure in this setting including poor T cell infiltration and a suppressive tumour microenvironment (TME) affecting CAR T cell efficacy.

T cell subset heterogeneity has been characterized in depth over the last decade, however direct head-to-head comparisons between vastly distinct classes of T cells and their utility for CAR T cell approaches have not been performed. Critically, beyond CD4 and CD8 classical T cells, non-conventional T cell subsets such as MAIT and gd T cells have higher organ-homing capacity and migrate preferentially to nonlymphoid tissue, where they can react rapidly to stimulus. Here, we hypothesise that MAIT cells and gd T cells may have several advantages over conventional T cells including their potential to be utilized in a third-party manner when generated from healthy donors and their increased cytotoxic capacity relative to conventional CD4 and CD8 T cells. Thus, we aim to holistically explore these T cell subsets and their propensity to act as CAR T cell therapeutics in the setting of solid tumours.

For this we will generate CD4, CD8, MAIT and gd T cell subsets expressing CARs of the same specificity and test their ability in parallel for in vitro cytotoxicity and cytokine secretion against tumour cells utilizing 2D and 3D cell culture models .We will identify the best layout of CAR constructs for armoured CAR approaches (activation domains and cytokine secretion) for the various T cell subsets and compare their in vivo ability to infiltrate and target solid tumours in mouse models. Within in vivo experiments, we will also exploit the amenability of unconventional CAR T cells as they can be selectively activated and expanded with TCR agonists such as antigens to enhance cell numbers or overall therapy persistence. In addition, we will utilize CRISPR-Cas9 technology to specifically override candidate molecules contributing to the immune-suppressive state of our generated CAR T cells (e.g. PD-1KO T cells) via approaches that have already been optimized within the host laboratories (Ref Giuffrida et al. 2021, Nature Communications).

The project will take place across 3 of Melbourne’s leading cancer and immunology institutes (PeterMac/PDI/ONJCRI) with lab rotations amongst these, leveraging the developed methodologies and expertise in these laboratories in unconventional T cell biology, cancer immunology, and CAR T cell development.


Improving response to immunotherapy

Improving response to immunotherapy

Supervisors:  A/Prof Doug Fairlie, Dr Conor Kearney, Erinna Lee

Laboratories: Molecular Immunology Laboratory, Cell Death and Survival Laboratory

Immunotherapy has reshaped the way we treat cancer. However, obstacles still exist including the inability to predict treatment efficacy, patient response and the development of resistance. Utilising the expertise of our joint labs in cancer immunology (Kearney) and membrane trafficking pathways (Lee/Fairlie), this PhD project will employ targeted CRISPR-based screening technologies to identify mechanisms that sensitise or inhibit tumour cells to T cell-mediated killing. For this project, the PhD candidate will utilise and develop skills in advanced molecular biology (in particular CRISPR screens), cell biology, membrane trafficking and cancer immunology.