Long-term research at UCLouvain has led to a possible new biomedicine: an anti-GARP monoclonal antibody. It may soon be clinically tested as a promising new treatment option for cancer patients.
She has been working here for 14 years. Since completing her PhD, UCLouvain Prof. Sophie Lucas, the head of a research group at the de Duve Institute, has focused on anti-tumour immune responses in cancer patients. Today, her research, conducted with the help of a growing team of researchers, has led to a promising drug that may soon be tested in clinical trials. Cancer immunotherapy is a growing research area. An American researcher, James Allison, and a Japanese researcher, Tasuku Honjo, have just been awarded the 2018 Nobel Prize in Physiology or Medicine for their work in immunotherapy!
As a professor in the Faculty of Medicine, Prof. Lucas has pursued her research at the de Duve Institute, a multidisciplinary centre home to more than 250 researchers. Prof. Lucas’s work is in immunology, one of the many fields of study the institute addresses. ‘We’re in a sector that is very close to medical applications and thus patients’, she observes. ‘My research is fundamental research, but I ask very concrete questions: How does the immune system react to tumour cells, and why, when the cancer advances, does it not work enough?’
First vaccines in the 1990s
‘I've been working on it for a while’, Prof. Lucas laughs. ‘Shortly before I began my thesis with Prof. Thierry Boon, he and his collaborators discovered tumour antigens. These small molecular determinants that are on the surface of tumour cells are likely to be recognised by the soldiers of our immune system: T-cells. This discovery, which dates back to the early 90s, has shown that the immune system is able to recognise and destroy tumour cells without attacking healthy cells. A major discovery that inspired my work.’
After earning her PhD, Prof. Lucas pursued her career abroad. When she came back to UCLouvain, things had changed a bit. ‘In the late 90s, the first tumour-based vaccines had been tested in cancer patients, to see if one managed to boost their anti-tumour immunity’, she recalls. ‘These vaccines were sometimes very effective but unfortunately not in the vast majority of patients. It was necessary to understand why anti-tumour immune responses were ineffective in these patients. This is when I decided to focus on a specific mechanism of immune system dysfunction against cancer.’ She cites a very particular type of T-cell, the ‘Treg’. Tregs protect our body from autoimmune diseases by blocking the activity of other T-cells that may be overzealous soldiers. ‘When you understand their natural function, you can very easily imagine that Tregs work too hard in cancer patients and prevent other lymphocytes from acting against the tumour’.
More than 14 years of research
In 2004, she began focusing on Treg functioning. ‘At first, I worked alone. Then, little by little, we became more numerous in my laboratory at the de Duve Institute. Today, we’re a dozen.’ The group’s first two publications in 2009 shed light on a mechanism of Treg functioning: the ‘GARP’ protein allows Tregs to emit an inhibitory messenger, TGF-beta, which acts on other T lymphocytes. In 2015, new results showed that monoclonal antibodies can block Tregs’ immunosuppressive function, by acting on the GARP protein and preventing it from emitting the inhibitory messenger.
The biotech company argenx, which specialises in the development of antibodies for therapeutic use, has been actively participating in this research since 2013. More recently, a pharmaceutical company, AbbVie, has also been participating. The development of an ‘anti-GARP’ antibody is underway: in August 2018 AbbVie announced the licensing of an antibody in order to continue the development of the biomedicine so that it can be clinically tested. This licensing follows on from scientific results obtained by Sophie Lucas’ research team and the firm argenx and published end of october 2018 in Science.
‘We imagined a biomedicine that belongs to the family of monoclonal antibodies’, Prof. Lucas says. ‘These antibodies are produced in laboratories but have the same structural and biochemical characteristics as those our bodies naturally produce to defend against infections. About 30 monoclonal antibodies are already used as biotherapeutic agents in Belgium. Each monoclonal antibody is directed against a specific target, and some are used for the treatment of cancer. The novelty of our antibodies? They target GARP and Tregs, an approach that has never been tested to date.’ Is Prof. Lucas's work complete? ‘Not at all! We always wonder how and when GARP works on cells, and not only on Tregs, but also B cells or platelets, where we also know it can be present...We are continuing our research in this area. To ask questions and seek answers to understand how something works – that’s the work of the researcher, she never stops.’
A glance at Sophie Lucas' bio
1994: Doctorate in Medicine, UCLouvain
1994-2002: Researcher, Ludwig Institute for Cancer Research (Brussels)
2000: Doctoral thesis, UCLouvain
2002-04: Researcher, Genentech, San Francisco (US)
Since 2004: Researcher, de Duve Institute, UCLouvain