Publish Date: 
Thursday, August 27, 2020 - 10:00

New autoimmune disease and cancer therapeutics edging closer to reality for patients

A career dedicated to rheumatoid arthritis has led Professor Ranjeny Thomas AM to the development of a potential new platform therapeutic for autoimmune diseases and a novel cancer vaccine. The Princess Alexandra Hospital rheumatology specialist and Arthritis Queensland Chair of Rheumatology with The University of Queensland Diamantina Institute (UQDI) has her research team based at the Translational Research Institute (TRI), where they are working on a range of immunology-based projects. TRI spoke to Professor Thomas about the pipeline of research she is preparing for clinical trials as well as her experience in translating research breakthroughs.

TRI: Can you explain to us how your platform therapeutic for autoimmune diseases works?

RT:  The therapeutic works by retraining people’s overactive immune systems, which are the cause of autoimmune diseases like rheumatoid arthritis. Essentially, it’ an antigen*-specific immunotherapy, which is delivered as an injectable drug.

This nanoparticle therapy consists of a liposome [or fat bubble] encapsulating a self-antigen* and the NF-kB inhibitor calcitriol [vitamin D3]. Injected liposomes drain to the lymph nodes, where they are taken up by immune system cells known as dendritic cells, which task lymphocytes* to control infection or to manage tolerance to self-tissues. After taking up the liposomes, calcitriol-modified dendritic cells suppress lymphocytes that are self-antigen reactive, which has a cascade effect to reprogram the immune attack on diseased tissues.

* Antigens are small proteins on the surfaces of cells. Immune cells known as lymphocytes constantly scour our body looking for antigens on invading microorganisms. When they find them, they trigger an immune response and the destruction of the foreign cells. In autoimmune diseases, lymphocytes mistakenly recognise ‘self-antigens’ on the body’s own cells and trigger an immune attack against these cells.

TRI: So, the therapy stops an individual’s immune system from malfunctioning and attacking his or her own body?

RT:  Yes, and the concept that we developed for rheumatoid arthritis is transferable to any autoimmune disease. We’re looking at tailoring it for several autoimmune diseases in parallel. If we can show safety, and how it works in at least one autoimmune disease, and the medical need is great in other disease areas as well, it will help build the case for development and investment.

TRI: Is the first disease you are applying this platform therapeutic to rheumatoid arthritis?

RT:  Yes, I trained as a rheumatologist, so I’m well versed in the significant health burden of this disease and limited treatment options. Through a long-standing, philanthropic partnership with Arthritis Queensland we’ve recently completed a first in-human trial for the rheumatoid arthritis version of the therapy, which was called DEN-181. We are just finishing the laboratory studies accompanying the trial, before submitting our results for publication. We have learnt an awful lot about the drug through this trial, and have been very encouraged by the data so far. For us, this first trial was very much about safety, and mechanism of action. We are now talking with potential industry partners and working hard with existing research grants to take our knowledge into the next phase.

TRI: What other diseases are you targeting with the drug?

RT:  I’m working towards clinical trials with another version of the therapy for Type 1 diabetes, in collaboration with Associate Professor Emma Hamilton-Williams and Dr Mark Harris [both also with UQDI at TRI]. This project is funded by a research grant from the Juvenile Diabetes Research Fund (JDRF) and the US Helmsley Foundation.

We recently announced a partnership with [biotech] CSL to develop and commercialise a version of the therapy for Sjogren’s Syndrome. This autoimmune disease of the salivary glands causes dry eyes and dry mouth in patients, and is often associated with rheumatoid arthritis and lupus. We are excited about the CSL deal. We have really enjoyed working with them on two other projects in the last few years.

Rheumatologist and postgraduate student, Dr Matt Terrill, is working on the autoimmune disorder, ANCA vasculitis—a rare and serious cause of kidney failure. [There are many types of vasculitis, most rare, but all cause inflammation of the blood vessels.]

It’s really about trying to piece together grant and industry funding to help us advance the treatment platform across the key areas of need among autoimmune diseases. I’m continually meeting with biotech companies and consumers to get feedback as to their autoimmune areas of interest, and on our technology. By working on several diseases at the same, it allows us to diversify the financial risk for existing and possible new industry partners, and ensures we can advance our knowledge base for the platform technology. It’s also been very productive scientifically to cross-fertilise work in Type 1 diabetes for example, with knowledge in rheumatoid arthritis, and vice versa.

TRI: How many years of research has it taken to develop the therapeutic platform?

RT:  It’s taken nearly 20 years of research and clinical studies. In 2001, we were working on dendritic cells, trying to understand what makes them function so well as antigen-presenting cells. We looked at pathways these cells activated and what happened when we blocked these pathways. That’s when we discovered that by blocking NF-kappa B, we could induce immune tolerance.

We used this immune tolerance discovery to create an initial cell-based therapy we called Rheumavax. This version of the therapy required a rheumatoid arthritis patient’s dendritic cells to be harvested then treated before being returned to the patient by intradermal injection. It was trialled in 18 patients in 2015, where we showed that a single injection was safe and regulated self-reactive lymphocytes. In parallel with this trial, we re-engineered the original therapy into its current form as an injectable drug. 

TRI: What can you tell us about the cancer vaccine you are working on?

RT:  The cancer immunotherapy that we have been developing in collaboration with the biotech company, Merck Sharpe and Dome in Australia [also known as MSD and Merck & Co. Inc in USA] since 2017, represents a new, tailored approach to treating cancer. This nanoparticle therapy is designed to target a specific population of dendritic cells, whose role is to stimulate lymphocytes to attack cancer cells or virally-infected cells. I can’t say much else at this stage, other than that I’ve really enjoyed working with MSD—it’s been a great partnership.

[The research team for this project includes Professor Riccardo Dolcetti with UQDI at TRI.]

TRI: Is your team working on any other research projects?

RT:  We have developed a laboratory model spondyloarthropathy [the name given to a family of inflammatory rheumatic diseases] to study the interaction between the gut microbiome [microscopic organisms that live in our intestinal system] and the immune system. We’re looking at possible causes of inflammatory bowel disease, psoriasis, uveitis and arthritis. It’s fascinating! We’ve discovered that with altered underlying genetics in the gut and microbe exposure, your gut microbiome can become skewed to promote pro-inflammatory bacteria. If the gut wall becomes permeable [often called ‘leaky gut’] it may allow bacterial products to cross into blood and cause joint inflammation. The genetically altered immune system struggles to fight this, so inflammation remains unchecked in the joints. There are many host immune and microbial factors involved in autoimmune diseases, which we are only just beginning to understand.

I am also involved in a national research collaboration, where we are recruiting at risk patients for the ‘Australian Autoimmune Biobank’.  We want to look at lifestyle and genetic risks for disease, and at behavioural interventions to help reduce the incidence of autoimmune diseases, and to improve the outcomes and quality of life for patients.

Additionally, during our Type 1 diabetes research, Dr Ahmed Mehdi in my team discovered a gene expression signature in infants that when combined with genetic risk score, identified children in the first year of life who had a high-risk of developing diabetes. This discovery could help us develop better screening tests to identify children at highest risk.

TRI: You’ve been working closely with The University of Queensland’s commercialisation company, UniQuest, since 2005 when they formed the start-up company, Dendright, as a vehicle to commercialise your original rheumatoid arthritis therapy. It’s obviously been a long journey, what advice can you share about your experiences in research translation?

RT:  Commercialising your research is definitely a hard road, but one that is also definitely very rewarding. There are wins and losses along the way, but it’s important to realise that the losses can lead to big learnings. No one goes straight to the top in the biotech arena. It takes a lot of resilience and perseverance to translate your research into a commercial product. Innovate rather than give up! It can be hard, though, to balance an academic and commercial career. An academic wants to know how and why something works, but in the commercial world you just need to know that it works. My advice to researchers is to remain focused on their end goal, and remember your commercial partner is running a business. You have to consistently perform and deliver results, and even then, the money does not always come. You have to be tough and learn to cope with criticism. Not many academic researchers get very far down this road, as they realise it’s not the career they want. The teamwork with UniQuest and their assistance has been essential and beneficial to keep me on this road, while still an academic.

TRI: Do you have any specific advice on dealing with industry? Is it something you can just leave to your institute’s commercialisation group?

RT:  You need to be willing to network with industry and understand their needs. I also believe you need to inspire people from within a biotech company to champion your research. I was the one who made the initial contact with Janssen Biotech through people I met a conference. I then introduced them to UniQuest as a potential industry-partner for my research. With MSD, I pitched to the company in Australia and then I went to the US to pitch again to groups based at their headquarters. In my experience, if the academic research is aligned to the potential partner’s research, you then really need to go to the home of the company and talk to lots of different groups and make contacts who can bring their excitement about your research to senior management. The academic also needs to be willing to make small or large pivots in his or her research direction to align with the needs of their partner. So it’s a multi-layered process of evaluation and negotiation that gets you over the line in the end.

TRI: Lastly, how does it help your research by being based at TRI?

RT:  TRI is a beautiful building with great facilities. It has especially good core facilities that allow you to do anything you need to do for your research. They stayed open for us during the COVID-19 crisis so we could continue our research and meet our milestones. So fantastic support! The new GMP cleanroom facilities will mean we can potentially manufacture our therapeutics in small batches for clinical trials. If TRI is able to expand and build additional facilities suitable for early-stage biotech companies, it may be possible to put together a consortium to manufacture the therapeutics suitable for early stage clinical trials in Australia. At the moment, the injectable nanoparticle-based therapeutics in development for treating autoimmune diseases are being manufactured to clinical trial quality by a company in Canada.

About Professor Ranjeny Thomas  

Professor Ranjeny Thomas AM is a graduate of the University of Western Australia, having received her MBBS in 1984, and then trained in Perth as a rheumatologist. Professor Thomas commenced a research fellowship with Peter Lipsky at Southwestern Medical Center, University of Texas in 1990, where she first identified and characterised human circulating dendritic cell precursors. Commencing in 1994 Professor Thomas is the inaugural Arthritis Queensland Chair of Rheumatology at University of Queensland Diamantina Institute, a consultant rheumatologist at Princess Alexandra Hospital and fellow of the Australian Academy of Health and Medical Sciences. Her research is focussed on the study of autoimmune disease and restoration of tolerance. Through this work, she developed and tested the first rheumatoid arthritis tolerising immunotherapy. She has also contributed major insights into the pathogenesis of spondyloarthropathy and autoimmune diabetes, leading to the development of disease biomarkers and innovative immunotherapies. Professor Thomas was awarded a Member of the Order of Australia in the General Division (AM) in recognition in 2020 for her significant service to medical education and research, and to rheumatology.

Research projects

  • Understanding the molecular control of dendritic cell function in tolerance
  • Pathogenesis of inflammatory bowel disease, psoriasis, uveitis and arthritis in a model of spondyloarthropathy: microbiota and the interaction with host immunity
  • Prediction of Rheumatoid arthritis risk and reducing risk in an at-risk cohort
  • Antigen-specific T cells in Rheumatoid Arthritis Synovial Tissue: Antigen specificity and function
  • Type 1 (Juvenile) Diabetes Interception with novel treatments (pre-clinical)
  • Pathogenesis of ANCA-vasculitis

Recent journal publications