Investigation of immune checkpoint blockade as novel treatment strategy for malignant pleural mesothelioma
24 May 2019
UAntwerp - Campus Drie Eiken - Building O - Auditorium O3 - Universiteitsplein 1 - 2610 WILRIJK (route: UAntwerpen, Campus Drie Eiken
Prof E. Smits, Prof J. Van Meerbeeck and Prof P. Pauwels
PhD defence Elly Marcq - Faculty of Medicine and Health Sciences (Presentation in English)
Malignant pleural mesothelioma (MPM) is a highly aggressive and nearly always fatal cancer that is in most afflicted patients causally associated with a previous, mostly professional, asbestos exposure.1 The highest incidence rates, around 30 cases per million inhabitants, are reported for Australia, Belgium and the UK2,3. 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 (20 up to 40 years) between asbestos exposure and MPM development and because asbestos is still being used in developing countries4 4.
The prognosis of patients diagnosed with MPM remains dismal with an untreated median overall survival of only 9-12 months and a 5-year survival rate of less than 5%4,5, due to its aggressive nature, its diagnostic delay and extended stage at presentation4,6. Chemotherapy consisting of a combination of a platinum compound and a folate antimetabolite, either pemetrexed or raltitrexed, have a significant but limited impact on overall survival7,8. Palliative platinum-antifolate chemotherapy results in a median overall survival of about 1 y compared with the 8– 10 months observed for chemotherapy-naïve patients7,9,10. Therefore, new therapeutic strategies are needed to complement the limited armamentarium against MPM6. The observation that the immune system can recognize and eliminate tumors is the impetus of the fast-growing research domain of tumor immunology and immunotherapy. For MPM specifically, the development of immunotherapy is supported by the recent knowledge that our immune system plays a critical role in its pathogenesis and in protection against MPM6,11,12. Immunotherapy of cancer has entered a new and exciting phase because of the discovery of immune checkpoint (ICP) receptors. In this doctoral thesis we investigated immune checkpoint blockade (ICPB) as novel treatment strategy for MPM. First of all, I focused on the tumor microenvironment and the ICP expression profile of tissue samples and effusions from MPM patients. The obtained results showed that ICPs are expressed in mesothelioma patient samples and identified TIM-3 and LAG-3 as promising new targets13,14. In vitro, we showed that (combined) ICPB might offer new opportunities to improve mesothelioma patient prognosis which is confirmed by preliminary in vivo data that show a survival benefit for mice treated with PD-L1 monotherapy and its combination with LAG-3 blockade. Further research will aim to unveil the working mechanisms of ICPB and the investigation of other treatments for advantageous combination strategies.
- 1. Robinson, B.W., Musk, A.W. & Lake, R.A. Malignant mesothelioma. Lancet 366, 397-408 (2005).
- 2. Bianchi, C. & Bianchi, T. Malignant mesothelioma: global incidence and relationship with asbestos. Ind Health 45, 379-387 (2007).
- 3. Bianchi, C., Brollo, A., Ramani, L. & Bianchi, T. Malignant mesothelioma in central and Eastern Europe. Acta Med Croatica 54, 161-164 (2000).
- 4. Robinson, B.W. & Lake, R.A. Advances in malignant mesothelioma. N Engl J Med 353, 1591-1603 (2005).
- 5. Musk, A.W., et al. Predicting survival in malignant mesothelioma. Eur Respir J 38, 1420-1424 (2011).
- 6. Bagia, M. & Nowak, A.K. Novel targeted therapies and vaccination strategies for mesothelioma. Curr Treat Options Oncol 12, 149-162 (2011).
- 7. Vogelzang, N.J., et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21, 2636-2644 (2003).
- 8. van Meerbeeck, J.P., et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol 23, 6881-6889 (2005).
- 9. van Meerbeeck, J.P., et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J.Clin.Oncol. 23, 6881-6889 (2005).
- 10. Muers, M.F., et al. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial. Lancet 371, 1685-1694 (2008).
- 11. Izzi, V., et al. Immunity and malignant mesothelioma: from mesothelial cell damage to tumor development and immune response-based therapies. Cancer Lett 322, 18-34 (2012).
- 12. Cornelissen, R., et al. New roads open up for implementing immunotherapy in mesothelioma. Clin Dev Immunol 2012, 927240 (2012).
- 13. Marcq, E., et al. Abundant expression of TIM-3, LAG-3, PD-1 and PD-L1 as immunotherapy checkpoint targets in effusions of mesothelioma patients. Oncotarget 8, 89722-89735 (2017).
- 14. Marcq, E., et al. Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma. Oncoimmunology 6, e1261241 (2017).