Research Elly Marcq

Abstract

Malignant pleural mesothelioma is a fatal cancer that is in most patients causally associated with asbestos exposure. Due to its aggressive nature and despite the effectiveness of conventional anti-cancer treatment, the prognosis of patients diagnosed with mesothelioma remains dismal with a median overall survival of only 9-12 months and a 5-year survival rate of only 5%. The current first-line chemotherapy, a combination of cisplatin and pemetrexed, only increases the overall survival by a few months. In the last decade, no improvement of survival has been achieved in this disease. Therefore, new therapeutic strategies are urgently needed in order to improve the prognosis and prolong the survival of mesothelioma patients. Smart combination strategies might improve anti-tumour response by interfering with different hallmarks of cancer and multiple immune escape mechanisms. In this research project tumour-induced immunosuppression will be tackled via two different pathways: PD-L1 immune checkpoint blockade will be used to reactivate silenced anti-tumour immune responses while blockade of the VEGF/VEGFR signalling pathway will be used to target the tumour vasculature in order to reduce angiogenesis, thereby reducing tumour growth. In addition, we plan to assess the positive impact that exercise may have on this combination strategy. Both immune checkpoint blockade and targeted anti-angiogenic treatments have been shown to improve survival in various cancer types. In addition, in vivo work and beneficial immunomodulatory effects suggest the potential of exercise as a non-invasive intervention to increase tumour sensitivity and to potentially synergise with immunotherapies. Therefore, we hypothesize that these treatments will enhance each other's efficacy and will effectively slow tumour growth. Furthermore, we will be the first to investigate the effect of exercise as a co-therapy with immune checkpoint blockade and anti-VEGF. Our data will demonstrate whether exercise as a co-therapy might be beneficial for tolerance and efficacy of our selected combination strategy. Our preclinical study is necessary to investigate a possible synergy of this novel treatment strategy combining immune checkpoint blockade, an anti-angiogenic compound, and exercise. The aim of this project is to meet the urgent need for a new treatment strategy improving both overall survival and quality of life of mesothelioma patients. Since the treatment methods described in this project have already been approved for use in cancer patients, our data can be easily translated into a clinical study.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Marcq Elly
• Fellow: Rovers Sophie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a fatal cancer that is in most patients causally associated with asbestos exposure. Due to its aggressive nature and despite the effectiveness of conventional anti-cancer treatment, the prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and a 5-year survival rate of only 5%. In the last decade, no improvement of survival has been achieved in this disease. Therefore, new therapeutic strategies are needed in order to prolong survival of MPM patients. With the discovery of immune checkpoints, immunotherapy of cancer has entered a new and exciting phase. Clinical studies in a.o. melanoma, renal cell cancer and lung cancer have shown that anti-PD-1 immunotherapy has durable clinical activity, even after treatment cessation, resulting in approval. Also, anti-PD-L1 immunotherapy has been approved for treatment of different cancers. Two clinical trials, investigating programmed death-1 (PD-1) or programmed death- ligand 1 (PD-L1) inhibition in mesothelioma (KEYNOTE-28 and JAVELIN trial, respectively), have already shown promising results with room for improvement. Smart combination strategies with other compounds might even improve the anti-tumor response by interfering with different hallmarks of cancer and multiple immune escape mechanisms. Tumor-induced immune suppression might also be tackled by targeting the vascular endothelial growth (VEGF) / vascular endothelial growth factor receptor (VEGFR) pathway, which induces tumor growth in MPM. In this research project tumor-induced immunosuppression will be tackled via two different pathways: immune checkpoint blockade will be used to reactivate silenced anti-tumor immune responses while blockade of the VEGF/VEGFR signaling pathway will be used to target the tumor vasculature in order to reduce angiogenesis thereby reducing tumor growth. Our preclinical study aims to investigate a possible synergy of a combination strategy with immune checkpoint blockade and an anti-angiogenic compound. Preclinical proof-of-concept that our investigated combination strategies have got anti-tumor effects will guide the rational design of future clinical studies. The new insights delivered by our preclinical study will contribute to saving considerable time and money in the clinical phase.

Researcher(s)

• Promoter: Marcq Elly

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous, mostly professional, asbestos exposure in most afflicted patients. Although preventive measures to limit asbestos use and exposure have been around for several decades, the incidence of MPM is still expected to increase over the next decade due to the long latency between asbestos exposure and MPM development. The prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and a 5-year survival rate of less than 5%, due to its aggressive nature and the limited effectiveness of any conventional anti-cancer treatment (i.e. chemotherapy, surgery and radiotherapy). The new chemotherapy regimens consisting of a combination of a platinum compound and the folate antimetabolites pemetrexed or raltitrexed have a significant but limited impact on overall survival in MPM. Therefore, new therapeutic strategies are needed to complement the limited armamentarium against MPM. The observation that the immune system can recognize and eliminate tumors is the impetus of the fast-growing research domain of cancer immunotherapy. With the discovery of immune checkpoints, immunotherapy of cancer has entered a new and exciting phase. Clinical studies in a.o. melanoma, renal cell cancer and lung cancer have shown that anti-PD-1 immunotherapy has durable clinical activity, even after treatment cessation, resulting in approval. Also anti-PD-L1 immunotherapy has been approved for treatment of different cancers. PD-1 and PD-L1 expression data in MPM of us and others laid the basis to evaluate their suitability as immunotherapeutic targets also in MPM. Two clinical trials, investigating PD-1 or PD-L1 inhibition in mesothelioma (KEYNOTE-28 and JAVELIN trial, respectively), have already shown promising results with room for improvement. Two other immune checkpoints, being lymphocyte activation gene-3 (LAG-3) and T-cell mucin immunoglobulin-3 (TIM-3), recently gained more interest since they have been described to be associated with T-cell tolerance and exhausted T cells that are infiltrating the tumor micro-environment. Our data on TIM-3 and LAG-3 expression in MPM effusions and on TIM-3 in MPM tissue samples identify both as promising new targets in MPM. Combined targeting of PD-1/PD-L1 with TIM-3 or LAG-3 was highly effective in controlling tumor growth in vivo in different other solid tumor models, providing a rationale to investigate combined blockade also in MPM. Smart combination strategies might improve the antitumor response by interfering with multiple immune escape mechanisms.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Marcq Elly

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive and fatal cancer that affects the membranes lining the lung and is mostly associated with previous exposure to asbestos. Till today, prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and currently available treatment methods have only a limited impact on it. Therefore there is an urgent need for new treatment methods. During my PhD project I will investigate the immune checkpoint programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2, as immunotherapeutic targets in MPM. It is presently unknown if blocking these targets have any effect in MPM but clinical trials in several tumor types have already shown promising results for PD-1 and PD-L1 immunotherapy.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: van Meerbeeck Jan
• Fellow: Marcq Elly

Research team(s)

Project type(s)

• Research Project