CANCER | 2020s
Discovery drives modern cancer and autoimmune therapies
Understanding self-tolerance to transform immunology
While most of us recognise the immune system as our body’s first line of defence against invaders like viruses and bacteria, the intricacies of its functions are less understood.
In the 80s and 90s, groundbreaking research by Professors Chris Goodnow and Tony Basten at the Centenary Institute fundamentally transformed the world’s knowledge of the science behind the immune system, laying the groundwork for innovative new therapies that would fight autoimmune diseases and cancer.
Harnessing new technologies
Key players in our defences are B cells, which produce antibodies to target and fight external threats, but sometimes our bodies can mistakenly recognise our own tissues as harmful, and our immune cells turn on them.
This breakdown in how B cells behave results in autoimmune diseases such as rheumatoid arthritis, lupus and some forms of anaemia.
The development of monoclonal antibody technology in the early 1980s opened a new frontier in the investigation of immune tolerance and autoimmune diseases. Monoclonal antibodies are engineered proteins that mimic the immune system, and they now represent a significant portion of new drug approvals by the Food and Drug Administration (FDA), particularly for auto-inflammatory diseases and cancer.
In the 1980s, Tony Basten was the Centenary Institute’s inaugural Executive Director. Under his leadership, he and the team harnessed monoclonal antibody technology to develop diagnostic tests for conditions like deep vein thrombosis and pulmonary embolism, as well as therapeutic antibodies for patients with Chronic Lymphatic Leukaemia.
In the 1990s, this work continued, while Tony’s research focused on B cell investigation with Chris Goodnow – work which would transform our understanding of how the immune system maintains self-tolerance (the process by which immune cells avoid attacking the body’s own tissues).
The behaviour of B cells
Both Tony Basten and Chris Goodnow are highly regarded for their pioneering work in transgenic research – the process of introducing foreign DNA into the genome to study gene function and model diseases.
Together, they were the first in Australia to harness this technology to develop critical transgenic models that allowed precise analysis of B cell tolerance.
“Using transgenic technology revolutionised our ability to understand the immune system. Typically, only about 1 in 1,000 immune cells can recognise a specific threat. However, using this new genetic technology, we could boost this recognition rate to more than 50%,” explains Tony.
Adopting this innovative technique proved to be a game-changer, leading to three landmark discoveries in how the body prevents immune cells from mistakenly attacking its own tissues. The research revealed that when challenged with a virus or bacteria:
- Some self-reactive (harmful) B cells are eliminated
- Some are put on ‘pause’ or ‘silenced’ so they don’t react (known as anergy)
- Some change and produce helpful antibodies instead
Research also found that these protective measures occur at various points in a B cell’s life, meaning that most self-reactive cells are eliminated, silenced, or changed before they can become a problem. This helps explain why autoimmune diseases don’t affect everyone.
These discoveries have been crucial in understanding autoimmune diseases and have established frameworks that remain central to immunological research today. For example, based on both monoclonal and B cell studies, it has become possible to look at the mechanisms underlying different autoimmune diseases in human subjects, such as Multiple Sclerosis, and to refine methods of treatment.
Tolerance checkpoints for cancer
The relevance of these discoveries now extends far beyond autoimmune diseases, heavily influencing cancer research. In cancer, the immune system can fail to recognise and fight malignant cells, partly because cancer cells can exploit immune checkpoints to evade attack. This creates a tolerance situation that allows cancer cells to thrive.
The research into B cell tolerance and immune regulation has informed the development of immune checkpoint inhibitors, which enable the immune system to target and destroy various types of cancer cells more effectively.
“By understanding how B cells and other immune cells are controlled, we can develop therapies that effectively enhance the body’s ability to fight cancer.”
These therapies now include antibodies that boost the potential of T cells to kill cancer targets or interrupt signals from cancer cells that block T cell killing.
It was the availability of new technologies and techniques at the Centenary Institute, combined with the curiosity and tenacity of its world-class researchers, that has helped to inspire, advance and accelerate immunological research.