Discovering new bait for the immune system may lead to additional treatments for melanoma

A collaborative study, led by ONJCRI and the Monash Biomedicine Discovery Institute (BDI) at Monash University, has uncovered new markers (HLA-associated peptides) that are uniquely present on melanoma tumours and could pave the way for therapeutic vaccines to be developed in the fight against melanoma.

Despite all improvements in melanoma treatment, every five hours one Australian dies because of the lack of effective treatment. A promising new approach harnesses the body’s own immune system to detect and kill tumour cells, through recognition of small tumour specific protein fragments (peptides) that decorate the surface of the tumour cells. The study, published in Cancer Immunology Research, a journal of the American Association for Cancer Research, has successfully identified thousands of peptides uniquely present on melanoma tumours that can be recognised by the immune system.

These observations have had an immediate clinical application, with the first clinical study on vaccination of melanoma patients using spliced peptides underway with collaborators at the Parker Institute for Cancer Immunotherapy, USA.

The study was co-led by ONJCRI's Dr Katherine Woods and Dr Andreas Behren (pictured) and BDI's Dr Pouya Faridi, Professor Anthony Purcell and Associate Professor Ralf Schittenhelm.

“We considered how a melanoma tumour might ‘look’ to the human immune system, under different growth conditions. The sheer scope of melanoma peptides that we identified in this study, many of which have never been reported before, was both surprising and inspiring,” said Dr Woods.

Findings have shown that some of these melanoma peptide markers are generated from a process called splicing. In splicing, a protein is first cut into small pieces (peptides) and then two of these pieces are pasted together to make a "spliced peptide". By identifying the exact spliced peptides, they can be synthesised outside of the body, then administered to patients to trigger the immune system into recognising and targeting tumours.

“The general goal of our study was to find new targets for melanoma treatment. We were unaware of the existence, prevalence and importance of these unique spliced peptides or if they could be recognised by the immune system. Now that we know they can, these peptides can be used as bait for the immune system to take action,” Dr Faridi said.

Dr Andreas Behren, Head of ONJCRI's Tumour Immunology Laboratory said: “Our finding, that we can successfully identify spliced melanoma peptides that are immunogenic across different patients, is very exciting.”

Professor Purcell notes: “Based on these studies, spliced peptide antigens have moved from an immunological curiosity to a whole new class of actionable targets not just in melanoma but other cancers as well. Using Dr Faridi’s new workflow we have been able to shine a spotlight on this previously ignored class of peptides opening up a previously untapped resource for immunotherapy and cancer vaccination. Indeed, the ubiquitous nature of this splicing process point towards this class of antigens playing roles in infectious disease, autoimmunity and allergy.

Read the paper in Cancer Immunology Research, a journal of the American Association for Cancer Research (DOI: 10.1158/2326-6066.CIR-19-0894)

Find out more about the Monash Biomedicine Discovery Institute

 


An easier way to analyse genes uncovered

Understanding the genetic make-up of cells, through a process known as RNA-sequencing, is an incredibly important process that allows researchers to better understand how cells work, grow and react with other cells. When analysing cancer cells, this research can help to identify where cancer starts, understand which treatments may be most effective for particular cells, or determining potential for cancer reoccurrence.

Currently, a process known as ‘Read Trimming’ is undertaken when analysing and mapping gene data through RNA-sequencing. In effect, this trimming removes adapter sequences and low-sequencing-quality bases (or in layman’s terms, some of the outliers of a data set) so that the analysis is focused on a more concentrated collection of gene data. While effective, this trimming does add significant data analysis time to each study and it is also unknown if the removal of the trimmed data impacts on the overall analysis or subsequent results of the remaining data set.

A study led by Prof Wei Shi, Head of our Bioinformatics and Cancer Genomics Laboratory, and Bioinformatician Dr Yang Liao, recently published in NAR Genomics and Bioinformatics Oxford Academic, has found that the read trimming process is not required for effective genome analysis. In fact, Wei and Yang found that by not undertaking read trimming (or only undertaking a ‘soft-clipping’), researchers can effectively analyse complete data sets faster, perform detailed analysis using less computational technology, while importantly providing equivalent or better data accuracy.

Wei said, “We found that adapter sequences can be effectively removed by a read aligner we developed via ’soft-clipping’ and that many low-sequencing-quality bases, which would be removed by read trimming tools, were rescued by the aligner”.

“Being able to conduct this analysis faster means that we also have access to results faster which is incredibly important when looking at scenarios for personalised medicine. Because doctors and their patients need to be able to access results as quickly as possible”, said Wei.

So, what does this mean for the future of RNA-sequencing?

“By sharing these findings, we hope that this will generate significant change to the way RNA-sequencing is performed by us and other researchers”, said Wei.

“We also hope that this will improve our ability to understand the properties and behaviours of different cells which can lead to more in-depth research and analysis of many cells, including cancer cells”.

 

Acknowledgments

This study has been possible thanks to the support of: Australian National Health and Medical Research Council, Walter and Eliza Hall Institute Centenary Fellowship sponsored by CSL, Victorian State Government Operational Infrastructure Support.

Wei and Yang also sincerely thank Prof Gordon K Smyth for suggesting this study.

 

Publication details

NAR Genomics and Bioinformatics - Oxford Academic: https://doi.org/10.1093/nargab/lqaa068

 

Image credit: Flavio Takemoto from FreeImages


Rare cancers clinical trial findings to have global benefit for patients

A phase II clinical trial led by the Olivia Newton-John Cancer Research Institute (ONJCRI), is showing exciting results for patients with rareupper gastrointestinal, neuroendocrine and gynaecological cancers.

The results of the rare upper gastrointestinal cancer cohort, that predominately enrolled patients who have biliary tract cancers like Anna pictured (and story below), have been published in JAMA Oncology. While results for trial participants with advanced neuroendocrine tumours were recently published in Clinical Cancer Research and the results for trial participants withadvanced gynaecological tumours were presented at the American Society of Clinical Oncology Annual Meeting - ASCO20 Virtual Scientific Program in May 2020.

The findings from this trial, which was generously supported by a grant from Bristol-Myers Squibb Ltd and Australian Government Medical Research Futures Fund, and championed by project partners Rare Cancers Australia, will have significant global implications for the treatment of patients with rare upper gastrointestinal, neuroendocrine and gynaecological cancers.

The current data demonstrates that trial participants who were treated with a combination of immune-stimulating anti-cancer drugs (Ipilimumab and Nivolumab)showed significant clinical benefit and life changing results.

Dr Oliver Klein, clinical trial co-lead, ONJCRI Clinician Fellow and Oncologist at Austin Health said, “These are promising results, in particular given that patients with rare cancers have limited treatment options compared to more common cancers”.

“Responses to immunotherapy were, as already seen in other malignancies, durable which contrasts with the generally short-lived responses obtained with chemotherapy”.

In this trial, ONJCRI, as the La Trobe University School of Cancer Medicine, investigated the use of the drugs Ipilimumab and Nivolumab as a combination immunotherapy which has so far not been trialled in patients with rare cancers. This combination treatment has already been shown to be an effective treatment for patients with metastatic melanoma, renal cell carcinoma, microsatellite unstable colorectal cancer and non-small cell lung cancer.

Globally, 20% of all cancer diagnoses, are for rare cancers. These patients currently have very limited access to treatment options and, as a result, have significantly reduced overall survival rate compared to patients with more common cancers.

Prof Jonathan Cebon, trial co-lead, Head, ONJCRI Cancer Immunobiology Cancer Program and Oncologist at Austin Health said, “This is an exciting day for people with rareupper gastrointestinal, neuroendocrine and gynaecological cancers”.

“As key players in the Australian cancer research community, we are very proud to be able to make this contribution in providing hope to patients with otherwise untreatable cancers.”

“This important trial is supported by our trial partners and generous Australians who donate to our research at ONJCRI,” said Prof Cebon.

The trial enrolment closed early in 2020 with trial participants currently in follow up. Ongoing translational research on tumour tissue and blood samples is aimed at identifying biomarkers to predict treatment response.

ONJCRI and the trial partners are also actively seeking additional opportunities and funding to expand the trial to more patients with rare cancers in rural and regional Australia.

 

ANNA’S STORY

Anna Anderson is grateful to be alive. When she was diagnosed with stage four gallbladder cancer her surgeon told her she had just months to live.

That was in October 2017.

The cancer was rare and aggressive and had metastasised to her liver.  With the outlook bleak, the mother-of-three was encouraged to get her affairs in order.

In January 2018 she joined the immunotherapy trial led by the Olivia Newton-John Cancer Research Institute, almost immediately things started to improve. Following less than a year on the trial, scans revealed Anna’s tumours had reduced to five per cent of their original size.

“The doctors are calling it a miracle,” she said. “I wouldn’t be here if not for the clinical trial”.

“I am incredibly grateful to the ONJCRI Team for the life changing work that they do. I hope that trial’s such as this will make it possible for others to benefit from the most up to date treatments modern medicine has to offer.”

 

Publication details

JAMA Oncology: https://jamanetwork.com/journals/jamaoncology/article-abstract/2768631

Clinical Cancer Research: https://clincancerres.aacrjournals.org/content/early/2020/06/12/1078-0432.CCR-20-0621

American Society of Clinical Oncology Annual Meeting - ASCO20 Virtual Scientific Program: https://meetinglibrary.asco.org/record/187511/abstract


Philanthropic funding to boost research into targeted therapies for colon cancer

Head of the Olivia Newton John Cancer Research Institute’s (ONJCRI) Cancer Therapeutics Development Group, Dr Ashwini Chand, along with ONJCRI Director and Head of the Cancer and Inflammation Program, Prof Matthias Ernst, have been awarded a coveted philanthropic grant to investigate new targeted therapies for colon cancer.

As successful applicants of the competitive Perpetual 2020 IMPACT grant program, Ashwini and Prof Ernst are set to further their translational research from the bench to the bedside.

Formed in 2018, the Cancer Therapeutics Development Group’s focus has been to discover pre-clinical drugs that are developed into new cancer treatments. By understanding how inflammatory cytokines contribute to the progression of colon cancers, we can find new ways of approaching the development of pre-clinical drugs that inhibit cancer growth and make the body’s immune cells more effective in killing cancer cells.

Through the generous support of the WALTER & NANCY LASCELLES MEMORIAL TRUST, The J and R McGauran Trust Fund, and the Perpetual Foundation - Eddy Dunn Endowment, the Cancer Therapeutics Development Group will be able to establish new cell-based technologies to further drug discovery efforts at ONJCRI. The funds will also enable the purchase of equipment that supports assay development and laboratory workflows. This will greatly enhance its capacity to progress our drug development programs.

“As a scientist, the ONJCRI provides a dynamic environment where I am able to translate my research discoveries into outcomes that will ultimately influence the health of patients,” says Ashwini.

“Bowel cancer is the second-most common cancer in men and women in Australia. With this generous funding, our research teams will be able to engage in further important colon cancer research specifically to develop targeted therapies for patients.”

Says Ashwini, “With the generous support of the Perpetual IMPACT scheme we will obtain a specific piece of equipment that allows us to making discoveries that will contribute to more efficient emergence of breakthrough cancer treatments. This generous funding will help us go much further.”

ONJCRI Director, Prof Ernst, says, “ONJCRI has enjoyed the generous and repeated support through the Perpetual IMPACT scheme, which is critical to the Institute’s mission to translate our discoveries at the laboratory bench into treatment that makes a difference to cancer patients.

“This support therefore not only provides us with opportunities to purchase new equipment and conduct critical experiments that we otherwise could not do, but it also gives the Institute and my colleagues a way to communicate with donors and those in philanthropy precisely what ONJCRI is continuing to do to help outsmart cancer.”

ONJCRI would like to thank the WALTER & NANCY LASCELLES MEMORIAL TRUST, The J and R McGauran Trust Fund, and the Perpetual Foundation - Eddy Dunn Endowment for their incredible support. 


Commercialisation Associate

Commercialisation Associate

  • Unique greenfield opportunity to establish a Translation Office
  • Exciting opportunity for an experienced, hands on Commercialisation Associate
  • Highly collaborative environment, with a focus on fostering partnerships with researchers, academia and industry
  • Generous salary packaging benefits

About the position

The Olivia Newton-John Cancer Research Institute (ONJCRI) has recently experienced significant growth, expanding research activities to include five distinct cancer research programs, genomic and single cell sequencing platforms, patient bio-banking and multi-platform capability. The ONJCRI Strategic Plan 2020-2024 is now focused on strengthening our position as a leading translational focused cancer research institute, with a key aspect being enhanced translation and commercialisation of the Institute’s research outputs.

ONJCRI is pleased to offer this opportunity for a Commercialisation Associate to make their mark by establishing a ‘fit for purpose’ Translation Office to promote the successful linking of research discoveries with commercial and translation outcomes. This dynamic role will report to and work closely and collaboratively with the Legal Counsel.

You will be responsible for:

  • Assessing the commercialisation potential of new technologies;
  • Proactively developing productive, professional relationships with key stakeholders with a focus on identifying commercial and clinical collaborations;
  • Intellectual Property (IP) capture, technology transfer and commercialisation across the Institute;
  • Managing the negotiation and execution of material, data and reagent transfer agreements, collaboration agreements, confidentiality agreements, commercialisation, licensing and assignment agreements;
  • Identifying and supporting opportunities to secure development and industry funding;
  • Development of templates, policies and agreements (working with the Legal Counsel as required) to enhance IP capture, collaboration and licensing.

About you

To succeed in this dynamic and challenging role you will have:

  • Strong strategic thinking and a proactive attitude;
  • A demonstrated track record in securing collaboration, licensing and technology agreements, including 2 years or more of biomedical industry experience in either biomedical product development, business development or technology transfer;
  • Proven agreement negotiation and drafting, including familiarity with IP related agreements and risk mitigation terms;
  • A PhD in a relevant biomedical discipline, with further research experience through post-doctoral or industry positions a clear advantage.

As an ONJCRI staff member, you will have access to professional development and mentoring, state of the art facilities and generous benefits including the ability to salary package.

To apply

Download the position description. Please forward your application with the subject heading Commercialisation Associate to Gabrielle Hirsch, Legal Counsel, with the following documents: Cover letter, Resume (clearly outlining relevant skills and experience) and the details of three referees (referees will only be contacted after interview).

Closing Date for Applications

17 July 2020


Postdoctoral Research Fellow Tumour Immunology Laboratory

Postdoctoral Research Fellow

Supervisor: Dr Andreas Behren

Laboratory: Tumour Immunology

  • Exciting new opportunity for an early to mid-career postdoctoral researcher
  • Actively participate in translational research which has real impact on patient outcomes
  • Generous staff benefits including the ability to salary package up to $18,550 per annum

About the position

This position is within the Tumour Immunology Laboratory (TIL) of the Cancer Immunobiology Program, which has a particular interest in malignant melanoma as a disease for the development of cancer immunotherapies, and understanding the characteristics of antigen systems for immune targeting.

The Lab’s most recent research identified molecules that are required for the activation of innate immune cells as highly expressed on cancer (Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells. Science 09 Jan 2020 DOI: 10.1126/science.aay5516). The successful applicant will work on deciphering the exact role that these molecules play in cancer immunity.

Additional research the Postdoctoral Research Fellow will focus on includes:

  • Melanoma cell biology, cellular plasticity, cellular immunology and the role of cancer antigens;
  • Analysis of human anti-cancer immunity that arises spontaneously in cancer patients;
  • Antigen processing & presentation - exploring the regulators of DC function including antigen uptake, processing, cross-presentation & T cell stimulation.

About you

To be considered for this role, you must have a PhD in science or related discipline, and background and experience in immunology is a must. Your research will require you to to perform a range of molecular biology techniques including:

  • Tissue and organ preparation with subsequent flow cytometry analysis;
  • Working with murine models;
  • Immunohistochemistry and/or immunofluorescence.

The successful candidate must have demonstrated experience with mouse work, flow cytometry/multi-parameter FACS, cellular immunology and tissue culture. Cell sorting experience, microscopy and imaging and cell biology would be highly regarded but not essential. You are self-motivated with the ability to think and work independently and also cooperatively, and will be expected to assist with supervision of research assistants and students within the lab. In addition, the postdoc will actively contribute to collaborations and the strategic vision and performance of the lab.

This position is fixed term for 2 years. As an ONJCRI staff member, you will have access to professional development and mentoring, state of the art facilities and generous benefits including the ability to salary package.

To apply

Download the position description. Please forward your cover letter and CV with 3 referee details, quoting the reference number ONJCRI-057/2020 to Dr Andreas Behren, Tumour Immunology Laboratory Head, via email at jobs@onjcri.org.au

Closing Date for Applications

31 July 2020

Due to anticipated high volume of applications, only shortlisted applicants will be contacted.