Immune checkpoint inhibitors in mesothelioma

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 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. LUMC / Geneeskund

Chemotherapy options versus "novel" therapies: how should we treat patients with malignant pleural mesothelioma

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 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.Pathogenesis and treatment of chronic pulmonary disease

Efficacy of nivolumab and ipilimumab in patients with malignant pleural mesothelioma is related to a subtype of effector memory cytotoxic T cells: Translational evidence from two clinical trials

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 aPD1 monotherapy failed to provide benefit in phase-III 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 an

Nose in malignant mesothelioma—Prediction of response to immune checkpoint inhibitor treatment

Pathogenesis and treatment of chronic pulmonary disease

Immune cells in mesothelioma microenvironment simplistic marker of response to nivolumab plus ipilimumab?

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 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

Tumor Junction Burden and Antigen Presentation as Predictors of Survival in Mesothelioma Treated With Immune Checkpoint Inhibitors

Introduction: The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other cancers. Because chromosomal rearrangements are common in mesothelioma and have neoantigenic potential, we sought to determine whether they are associated with survival in patients treated with immunotherapy.Methods: Pleural biopsies of mesothelioma after at least one line of therapy were obtained from patients (n = 44) before treatment with nivolumab alone (NCT29908324) or in combination with ipilimumab (NCT30660511). RNA and whole-genome sequencing were performed to identify the junctions resulting from chromosomal rearrangements and antigen processing and presentation gene set expression. Associations with overall survival (OS) were estimated using Cox models. An OS cutoff of 1.5 years was used to distinguish patients with and without durable benefit for use in receiving operating characteristic curves.Results: Although tumor junction burdens were not predictive of OS, we identified significant interactions between the junction burdens and multiple antigen processing and presentation gene sets. The "regulation of antigen processing and presentation of peptide antigen" gene set revealed an interaction with tumor junction burden and was predictive of OS. This interaction also predicted 1.5-year or greater survival with an area under the receiving operating characteristic curve of 0.83. This interaction was not predictive of survival in a separate cohort of patients with mesothelioma who did not receive immune checkpoint inhibitors.Conclusions: Analysis of structural variants and antigen presentation gene set expression may facilitate patient selection for immune checkpoint inhibitors. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc.Pathogenesis and treatment of chronic pulmonary disease

Tumor Junction Burden and Antigen Presentation as Predictors of Survival in Mesothelioma Treated With Immune Checkpoint Inhibitors

Introduction: The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other cancers. Because chromosomal rearrangements are common in mesothelioma and have neoantigenic potential, we sought to determine whether they are associated with survival in patients treated with immunotherapy.Methods: Pleural biopsies of mesothelioma after at least one line of therapy were obtained from patients (n = 44) before treatment with nivolumab alone (NCT29908324) or in combination with ipilimumab (NCT30660511). RNA and whole-genome sequencing were performed to identify the junctions resulting from chromosomal rearrangements and antigen processing and presentation gene set expression. Associations with overall survival (OS) were estimated using Cox models. An OS cutoff of 1.5 years was used to distinguish patients with and without durable benefit for use in receiving operating characteristic curves.Results: Although tumor junction burdens were not predictive of OS, we identified significant interactions between the junction burdens and multiple antigen processing and presentation gene sets. The "regulation of antigen processing and presentation of peptide antigen" gene set revealed an interaction with tumor junction burden and was predictive of OS. This interaction also predicted 1.5-year or greater survival with an area under the receiving operating characteristic curve of 0.83. This interaction was not predictive of survival in a separate cohort of patients with mesothelioma who did not receive immune checkpoint inhibitors.Conclusions: Analysis of structural variants and antigen presentation gene set expression may facilitate patient selection for immune checkpoint inhibitors. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc