Research Jonas Van Audenaerde

Abstract

COVID-19, a disease caused by an infection with SARS-CoV-2, has a broad range of clinical presentations varying from asymptomatic to severe bilateral pneumonia and even death. The risk to develop severe COVID-19 as well as the mortality is the highest in the elderly and in people with a pre-existing condition such as cancer. Hence, cancer patients were prioritized for COVID-19 vaccination even though data on the effectiveness and safety was not available as immunocompromised patients, like cancer patients, were excluded from vaccine approval trials. Since the approval of different COVID-19 vaccines, our group as well as many others performed studies to map the immunological responses of cancer patients after vaccination. In general cancer patients have reduced humoral immune responses after COVID-19 vaccination, nevertheless the vaccines are well-tolerated. As COVID-19 is evolving to be an endemic virus, it is important to map all parts of the vaccination-induced immune response. While most studies report IgG levels and neutralizing antibodies when investigating the humoral immunity, IgA antibodies are important for mucosal immunity and eliminate pathogens immediately at the point of entry (e.g. respiratory system). In the context of influenza, IgA serum levels have been correlated with influenza vaccine efficacy and influenza-specific IgA has been shown to be more effective in preventing infections in mice and humans compared with influenza-specific IgG. Therefore the level of IgA in serum may serve as an indicator of host immune response and might possible be a better predictor for protection against respiratory viruses compared to IgG, but studies on IgA production upon COVID-19 vaccination are lacking. Additionally, studies assessing the role of innate immune cells in vaccination-induced immune response are scarce. A recent study provided the first hints towards the predictive capacity of NK cells -innate lymphocytes that are crucial for mediating anti-viral responses- for vaccine-induced immunity in both healthy individuals and immunocompromised patients without cancer. This is in line with other research highlighting the potential of the activity level of NK cells to serve as a biomarker for a functional immune response, but as NK cells are involved in anti-tumor responses and might be affected by anti-neoplastic treatment, it is currently unknown if these findings can be applied in a cancer population. Hence, the aim of the current study is to gain a more in depth understanding of the different aspects of vaccination-induced immunity against SARS-CoV-2 in cancer patients focusing on both IgA levels and NK cells. This will help guiding COVID-19 vaccination strategies for cancer patients during future endemic outbreaks by providing knowledge on the state of the immune system of cancer patients and their response upon vaccination. Furthermore, the obtained insights can be used to improve vaccination strategies for cancer patients for other viruses as well as when novel viral pathogens emerge.

Researcher(s)

• Promoter: Vandamme Timon
• Co-promoter: Van Audenaerde Jonas
• Fellow: Debie Yana

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Prospects for cancer patients are certainly ameliorated in the past decade, especially thanks to the advances in the field of immunotherapy. However, it is important to note that many challenges remain. More specific, the majority of patients in need of better treatment options does not respond to immune checkpoint blocking therapy while CAR T cell therapy has only limited efficacy against solid tumours and on top causes severe side effects. Also, many tumours produce immunosuppressive cytokines like TGFβ, hampering current immunotherapy approaches. To address the challenges, our lab has developed over the past five years a TGFβ-resistant, Interleukin-15 producing CAR NK cell therapy which targets the CD70 protein. CAR NK cells have the important advantage that – contrary to CAR T cells – they do not cause severe side effects. Moreover, they can be produced as off-the-shelf therapy and do not require the same cumbersome production process as CAR T cells. The CD70 protein is also a ideal target since it is highly expressed in both leukaemia and solid tumours. This project has two main objectives. First, we want to gather the necessary preclinical data showing that our CAR NK cells are also successful against acute myeloid leukaemia. Secondly, we want to scale-up the production process of our CAR NK cells from research-grade to GMP-grade as this is a requirement for entering the clinical trial stage.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Campillo Davó Diana
• Co-promoter: De Waele Jorrit
• Co-promoter: Lion Eva
• Co-promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Paediatric high-grade gliomas (pHGG) represent the leading cause of cancer-related death in childhood. With the current standard of care (SOC), the prognosis is very dismal with a 5-year survival rate of less than 20%. There is an urgent need to develop new treatment strategies to improve the overall survival. Immunotherapy to treat cancer is now considered to be one of the main pillars in cancer management and adoptive cell transfer has had enormous successes in the paediatric field in haematological malignancies. However, the therapeutic efficacy, as seen in haematological malignancies, has been lacking in solid tumours so far due to several challenges. pHGG are known for their cold immunological tumour microenvironment with few tumour infiltrating lymphocytes, have a high heterogeneity in antigen expression and are difficult to access due to the blood-brain barrier. Therefore, we aim to develop a novel therapy to overcome these challenges by combining the locoregional administration of our designed cell therapy with an immune priming strategy. We hypothesize that this combination therapy can increase the therapeutic efficacy of the SOC against pHGG.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: De Waele Jorrit
• Co-promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The aim of this project is to develop a novel, safe and ready-to-use therapy for the treatment of cancer patients. Therefore, we will test the efficacy of the novel therapy in the lab in different ways.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Paediatric high-grade gliomas (pHGG) represent the leading cause of cancer-related death in childhood. With the current standard of care (SOC), the prognosis is very dismal with a 5-year survival rate of less than 20%. There is an urgent need to develop new treatment strategies to improve the overall survival. Immunotherapy to treat cancer is now considered to be one of the main pillars in cancer management and adoptive cell transfer has had enormous successes in the paediatric field in haematological malignancies. However, the therapeutic efficacy, as seen in haematological malignancies, has been lacking in solid tumours so far due to several challenges. pHGG are known for their cold immunological tumour microenvironment with few tumour infiltrating lymphocytes, have a high heterogeneity in antigen expression and are difficult to access due to the blood-brain barrier. Therefore, we aim to develop a novel therapy to overcome these challenges by combining the locoregional administration of our designed cell therapy with an immune priming strategy. We hypothesize that this combination therapy can increase the therapeutic efficacy of the SOC against pHGG.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: De Waele Jorrit
• Co-promoter: Van Audenaerde Jonas
• Fellow: Vanheeswijck Liesbeth

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In the past five years, RNA therapeutics have witnessed a true revolution. Several RNA-based therapies have been approved for the treatment of genetic diseases, with unprecedented successes, as in spinal muscular atrophy. Moreover, the past year showed the world that RNA-based therapies, namely mRNA vaccines, can be the answer to a worldwide pandemic and save the lives of millions. RNA therapies are however lagging behind in clinical oncology. The overarching aim of this multi-armed project is to develop RNA-based cancer treatments. In parallel, the development of immune checkpoint inhibitors has revolutionized cancer care, but its success remains limited to a subset of patients. Altogether, for 60 percent of the eight million new cancer patients diagnosed in Europe each year, including almost all children with solid tumors, there is no EMA- or FDA-approved immunotherapy option, and they are left out of the circle of hope. In response, CANCERNA aims to build on these two breakthroughs and apply RNA-based therapeutics to overcome key barriers to unfold successful anti-cancer immune responses. Our two key objectives are: on one hand, harness the modulation of RNA processing to enhance the accessibility and immune susceptibility of the tumour and its microenvironment. While on the other hand, enhance the activity of the immune system by retargeting immune effector cells and developing personalized mRNA vaccines. The project will focus on two cancer types: acute myeloid leukemia and uveal melanoma. The collective knowledge of our consortium of RNA scientists, clinicians and biotech-pharma experts in RNA processing, RNA drug design and delivery, biocomputing and immuno-oncology provides a unique opportunity to significantly advance novel RNA technologies into successful cancer therapies.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: De Waele Jorrit
• Co-promoter: Lion Eva
• Co-promoter: Pauwels Patrick
• Co-promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

Over the last decade, immunotherapy has had an unseen impact on the outcome of cancer patients. However, many hurdles remain. For example, the majority of patients in need of better treatment options does not respond to PD-1 blockade, while CAR-T cells remain ineffective in solid tumours as monotherapy and go hand-in-hand with often severe cytokine release syndrome and neurotoxicity. On top of that, most tumours produce large amounts of cytokines in their microenvironment which fiercely suppresses both present and infiltrating immune cells. To address these obstacles, our lab has developed over the last five years a CAR-NK cell therapy which targets the CD70 protein. CAR-NK cells have the advantage over CAR-T cells of being safer since no toxicities were observed in their first clinical trials and their ability to be produced off-the-shelf. Moreover, we have proven that CD70 is a highly attractive target for several cancer types and is on top more and more recognised as a promising pan-cancer target. For this project, two main objectives have bene formulated: first we want to optimise the production process of the CAR-NK cells in such a way that they are being produced according to GMP regulations. The latter is necessary to allow usage in a clinic trial. Secondly, we want to collect the necessary preclinical data proving the effectiveness of our CD70 CAR-NK cell therapy in acute myeloid leukaemia. This way, we want to formulate a GMP-grade, as automated as possible, CAR-NK production process and have acquired all required preclinical data necessary to start an early-phase clinical trial.

Researcher(s)

• Promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The purpose of this translational research project is the development of a new combination immunotherapy for pancreatic cancer. We will focus on both activation of the immune system and at the same time inhibition of immune suppression. Importantly, not only the tumour cells themselves but also the pancreatic stellate cells which form a barrier around the tumour. by this unique focus, our innovative therapeutic approach has a higher chance of success.

Researcher(s)

• Promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer related death in the western world and incidence is still rising. Due to its rapidly progressive nature and lack of early symptoms, up to 80% of the patients present itself late with advanced or metastatic disease. This results in an extremely poor prognosis and a 5-year survival below 5%. Current treatment options for PDAC are limited since only 10-15% of the patients are eligible for curative surgical resection. The remaining patient population is treated with chemotherapy which has only modest improvements in survival due to chemoresistance in the majority of patients. The tumour microenvironment (TME) is believed to be a major confounding factor involved in failure of different therapeutic strategies. A hallmark of this TME in PDAC is the strong desmoplastic reaction which results in a dense fibrotic/desmoplastic stroma that surrounds the pancreatic cancer cells (PCC). By acting as a mechanical and functional shield around the tumour, it plays a central role in the development, progression and invasion of PDAC and also creates an immunosuppressive TME. In this strategic basic research project, novel combination immunotherapies will be investigated in search for better treatment options for PDAC patients. Both immune stimulation and inhibition of immune suppression will be employed, with a special focus on the TME.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Peeters Marc
• Fellow: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a common gastrointestinal malignancy characterized by rapid progression, resulting in poor outcome and a 5-year survival rate of less than 5%. There are no effective therapies for PDAC, except for surgical resection which has a minor impact on survival. In order to improve clinical outcome, new therapeutic strategies are needed. PDAC is characterized by a dense desmoplastic reaction, primarily reflecting the activation of pancreatic stellate cells (PSC). PSC become activated in response to growth factors, oxidative stress and changes in tissue plasticity. Activated PSC within the PDAC stroma have an impact on the migration of immune cells towards malignant lesions, playing an important role in modulation of the crosstalk between neoplastic, stromal and immune cells. In PDAC, the ability of the immune system to identify and eliminate neoplastic cells is compromised, suggesting that an immunosuppressive environment is established. Immunotherapy can potentially be a powerful new component of PDAC treatment. However, in order to obtain immune-mediated elimination of PDAC, most likely immune stimulation must be combined with a strategy that overcomes the immunosuppressive environment. Further study of the mechanisms by which immunosuppression is initiated in PDAC, and ways to overcome it, will facilitate the development of this treatment option. Here, we will focus on unraveling the interactions between PSC, innate immune cells and tumor cells in order to identify new therapeutic targets. Experiments will be performed in vitro and in vivo.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Van Audenaerde Jonas

Research team(s)

Project type(s)

• Research Project