Introduction: Malignant pleural mesothelioma (MPM) is a malignant disease of the pleura which recently can be treated with immune checkpoint inhibitors (ICI). To optimize this treatment, a better... Show moreIntroduction: Malignant pleural mesothelioma (MPM) is a malignant disease of the pleura which recently can be treated with immune checkpoint inhibitors (ICI). To optimize this treatment, a better understanding of the tumor micro environment is needed. We investigated subgroups of immune cells in subsequent tumor biopsies of patients treated with ICI. Methods: Biopsies from MPM patients included in two clinical ICI trials (nivolumab alone and an ipilimumab/nivolumab combination) were examined. At baseline and after 6 weeks of treatment, pleural biopsies were taken to examine the tumor microenvironment (CD20+, CD4+, CD8+, FoxP3+ and PD-1+ ). Cell density was defined as the number of marker positive cells per mm(2). Radiological responses were evaluated as partial response, stable disease or progressive disease according to modified RECIST criteria. Results: Thirty-four and 36 patients were included in the nivolumab and ipiliumumab/nivolumab trial respectively. In the nivolumab trial, no significant differences in cell densities were seen in baseline biopsies of patients with partial response versus progressive disease. In contrast, in the ipilimumab/nivolumab trial, a higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells at baseline was significantly correlated with partial responses. On-treatment biopsies of both trials did not show significant changes when compared to baseline biopsies. Conclusion: Biopsies from patients responding to nivolumab plus ipilimumab treatment show a significant higher cell density of CD4+, CD8+, FoxP3+ and PD-1+ cells, without a change after 6 weeks of treatment. This observation is a first step in exploring the tumor microenvironment as predictor of response in ICI treatment in MPM. Show less
Mesothelioma is an aggressive tumor originating from the mesothelial cells of the pleural or peritoneal cavity. This thesis focuses on the treatment of pleural mesothelioma. For long, chemotherapy... Show moreMesothelioma is an aggressive tumor originating from the mesothelial cells of the pleural or peritoneal cavity. This thesis focuses on the treatment of pleural mesothelioma. For long, chemotherapy has been the standard of care, leading to an overall survival of about 15 months. In this thesis, a phase 2 trial is performed using two checkpoint inhibitors, nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4), to treat recurrent mesothelioma after at least one line of chemotherapy. Of the 34 patients evaluable for response 29% had a partial response and 38% patients had stable disease, so 68% of patients achieved disease control, the primary endpoint. These results exceeded expectations and rejected the alternative hypothesis. In part III translational research was performed on blood samples, pleural biopsies and breath analyses at baseline and after 6 weeks of treatment. In order to find markers of response and try to explain how immunotherapy affects the tumor microenvironment and immune cell subsets of the peripheral blood. Show less
Disselhorst, M.J.; Vries, R. de; Quispel-Janssen, J.; Wolf-Lansdorf, M.; Sterk, P.J.; Baas, P. 2021
IntroductionRecent clinical trials with immune checkpoint inhibitors (ICIs) have shown that a subgroup of patients with malignant pleural mesothelioma (MPM) could benefit from these agents. However... Show moreIntroductionRecent clinical trials with immune checkpoint inhibitors (ICIs) have shown that a subgroup of patients with malignant pleural mesothelioma (MPM) could benefit from these agents. However, there are no accurate biomarkers to predict who will respond. The aim of this study was to assess the accuracy of exhaled breath analysis using electronic technology (eNose) for discriminating between responders to ICI and non-responders.MethodsThis proof-of-concept prospective observational study was part of an intervention study (INITIATE) in patients with recurrent MPM who were treated with nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4). At baseline and after six weeks of treatment, breath profiles were collected by an eNose. Modified Response Evaluation Criteria in Solid Tumors were used to assess efficacy at 6-month follow-up. For data processing and statistics, we used independent t-test analyses followed by linear discriminant and receiver-operating characteristic (ROC) analysis.ResultsExhaled breath data of 31 MPM patients who received nivolumab plus ipilimumab were available at baseline. There were 16 with and 15 without a response after 6 months of treatment. At baseline, breath profiles significantly differed between responders and non-responders, with a cross validation value of 71%. The ROC-AUC after internal cross-validation was 0.90 (confidence interval: 0.80–1.00).ConclusionAn eNose is able to discriminate at baseline between responders and non-responders to nivolumab plus ipilimumab in MPM, thereby potentially identifying a subgroup of patients that will benefit from ICI treatment. Show less
Mankor, J.M.; Disselhorst, M.J.; Poncin, M.; Baas, P.; Aerts, J.G.J.V.; Vroman, H. 2020
Background: Combined immune checkpoint inhibitor (ICI) treatment targeting PD-1 and CTLA-4 was suggested to yield clinical benefit over chemotherapy in malignant pleural mesothelioma (MPM), whereas... Show moreBackground: Combined immune checkpoint inhibitor (ICI) treatment targeting PD-1 and CTLA-4 was suggested to yield clinical benefit over chemotherapy in malignant pleural mesothelioma (MPM), whereas aPD-1 monotherapy failed to provide benefit in phase-Ill trials. Success of ICI depends on the presence and activation of tumor-specific T cells. Therefore, we investigated whether T-cell characteristics are underlying clinical efficacy of ICI treatment in MPM.Methods: Comprehensive immune cell profiling was performed on screening and on treatment peripheral blood samples of mesothelioma patients treated with nivolumab (aPD-1) monotherapy (NCT02497508), or a combination of nivolumab and ipilimumab (aCTLA-4) (NCT03048474).Findings: aPD-1 /aCTLA-4 combination treatment induced a profound increase in proliferation and activation of T cells, which was not observed upon aPD-1 monotherapy. Moreover, patients that responded to combination treatment had low frequencies of naive CDS T cells and high frequencies of effector memory CDS T cells that re-expressed RA (TEMRA) at screening. The frequency of Granzyme-B and Interferon-y producing TEM-RAs was also higher in responding patients.Interpretation: High proportions of TEMRAs and cytokine production by TEMRAs before treatment, was associated with a better clinical outcome. TEMRAs, which likely comprise tumor-specific T cells, tend to require blockage of both aPD-1 and aCTLA-4 to be reactivated. In conclusion, peripheral blood TEMRAs can play a key role in explaining and predicting clinical benefit upon aPD-1/aCTLA-4 combination treatment. (C) 2020 Published by Elsevier B.V. Show less
Today there are several options for the treatment of patients with malignant pleural mesothelioma (MPM). The therapeutic arsenal has expanded from only chemotherapy with or without surgery in... Show moreToday there are several options for the treatment of patients with malignant pleural mesothelioma (MPM). The therapeutic arsenal has expanded from only chemotherapy with or without surgery in selected cases to a variety of new compounds that target the malignant cell or its micro-environment. Immunotherapy has been the latest achievement and now single arm and randomized studies are being presented. A renewed interest has occurred in the combination of surgery, chemotherapy and radiation therapy. In this review we present the available data on previous and running studies and try to give a recommendation how to select the best patient for the most optimal therapy. Show less
