Preclinical investigation of immunotherapy and VEGF-targeted therapy in combination with voluntary exercise as novel treatment strategy for malignant pleural mesothelioma.

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.

Keywords:IMMUNE CHECKPOINT INHIBITOR, VOLUNTARY EXERCISE, MESOTHELIOMA, ANGIOGENESIS

Disciplines:Adaptive immunology, Cancer biology, Cancer therapy