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Project

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

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.
Date:1 Apr 2020 →  31 Mar 2021
Keywords:MOUSE MODELS, ONCOLOGY, IMMUNOLOGY
Disciplines:Adaptive immunology, Innate immunity, Cancer biology, Cancer therapy