On 14 December, Prof. Sophie Lucas and her team at the UCLouvain de Duve Institute received the prestigious GSK Award from the Wallonia-Brussels Federation Academy of Medicine for their promising research and discoveries in the field of cancer immunotherapy.
Every two years, the Academy of Medecine’s GSK Award recognises work in vaccinology and immunology that contributes significantly to basic or clinical knowledge and might impact patients. This year Sophie Lucas and her UCLouvain de Duve Institute research team won this prestigious award for their decade of research on tumour immunology.
Immunotherapy: a promising alternative
This de Duve Institute research team studies the immune response that cancer patients can use against their own tumour. ‘In the long run,’ Prof. Lucas says, ‘the goal is to try to manipulate immune responses to make them more effective and allow the patient to reject tumour cells.’ This would be an incredible breakthrough in the field of immunotherapy, which is itself a great alternative to cancer therapies that target tumour cells, such as chemotherapy or radiation therapy. Immunotherapy stimulates immune system cells to turn against the patient’s tumour and destroy it.
‘Tregs’: research starting point
Today, Prof. Lucas is proud to have developed with her team a new drug that is just starting to be tested in cancer patients for targeting their immune systems. To arrive at this magnificent result (which still has some way to go), the de Duve Institute team made major discoveries over the last ten years. ‘In 2004-05, we wondered whether certain immune system cells could play a negative role in cancer patients’. In other words, do some cells decrease antitumour immune responses? The team suspected that regulatory T cells (Tregs) could indeed be very toxic to cancer patients. Tregs regulate the immune system so much that they reduce the effectiveness of immune cells that are supposed to kill cancer cells. As a result, the immune system is no longer effective against cancer.
Discovery of TGF-beta messenger
During this first discovery, no one knew how Tregs worked. How do they reduce the effectiveness of antitumour immune cells in humans? In Prof. Lucas's lab, researchers cloned and cultivated in vitro Tregs to come up with a major breakthrough: Tregs work by producing an inter-cellular messenger. This molecule, called TGF-beta, transmits messages from Tregs to other cells. TGF-beta has the ability to inhibit antitumour immune cells, thus decreasing their effectiveness. The culprit was thus revealed, but in 2009, the team realised Tregs require another molecule, located on their surface, to produce TGG-beta, a kind of accomplice, called GARP. In just a few years, Prof. Lucas's team identified Tregs, TGF-beta and GARP as three major players that reduce antitumour immune responses.
New therapeutic tool
The team then sought to develop therapeutic agents (monoclonal antibodies) that prevent Tregs from emitting the TGF-beta messenger via GARP. In 2015, they obtained such a therapeutic tool, by deriving a monoclonal antibody capable of blocking GARP and the production of TGF-beta by Tregs. In 2018, the team was able to visualise the three-dimensional structure of GARP that binds TGF-beta to the surface of Tregs. At the same time, the researchers understood how their monoclonal antibody could prevent the release of the TGF-beta inhibitory messenger, and thus play a potential role as a drug.
Beginnings of clinical trials
Through all of these observations, the team performed tests to see whether the anti-GARP monoclonal antibody could cure cancer in mice. ‘The results aren’t yet published’, Prof. Lucas says. ‘It seems however that it works in mice. It succeeds in inducing the rejection of certain tumours.’ The promising discovery aroused the interest of a pharmaceutical company, which licensed the antibodies in August 2018. ‘Clinical trials in humans have just begun. In July 2019, cancer patients were injected with our anti-GARP monoclonal antibodies.’
The next steps? ‘There are many’, Prof. Lucas says. ‘Today, many avenues are available to us’. The first step: If clinical trials yield encouraging results, the team will have access to biopsies taken from patients treated with the anti-GARP antibody, analyse them, and verify whether the molecule works as they think it does. ‘That’ll also be an opportunity to see whether we can combine our antibodies with other antitumour drugs to improve their effectiveness.’ Second step: Whatever the results of the clinical trials, the team will continue to work on very basic aspects of TGF-beta and GARP biology. ‘It's not just Tregs that produce TGF-beta via GARP. We know that other cells do it too, but we don’t know why.’ What is the function of GARP and TGF-beta produced by other cells? Is it to systematically decrease immune responses? Or do these actors play other roles? ‘To better understand the biology of these amazing molecules, we’ll expand our area of expertise, which is currently focused primarily on cancer, to chronic infections or autoimmune diseases, for example’. When could an effective drug appear? ‘It’ll take another three to five years to see whether our drug shows signs of efficacy without excessive toxicity for cancer patients.’ The award adds to the team’s motivation to strive for an immunotherapy cure for cancer.
A glance at Sophie Lucas' bio
Sophie Lucas earned two UCLouvain PhDs, one in medicine in 1994, the other in biomedical sciences in 2000 for her work on tumour immunology in the laboratory of Prof. Thierry Boon at the Ludwig Institute for Cancer Research. She then completed a two-year postdoctoral fellowship at the Genentech biotechnology company in San Francisco, where she studied new cytokines and their receptors in Frédéric de Sauvage's laboratory. In 2004, she established her own research team at UCLouvain’s de Duve Institute. An FNRS research associate since 2008, she became a professor of cancer immunotherapy at UCLouvain in October 2016. Her research focuses on the role of regulatory T cells in suppressing immune responses in humans, more specifically cancer patients. Her laboratory discovered a mechanism for regulating T cells to produce an immunosuppressive cytokine known as TGF-beta. The mechanism requires a protein called GARP, and GARP can be therapeutically targeted with monoclonal antibodies. This research creates possibilities for developing a new approach to cancer immunotherapy.