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Objectives: Nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) is a new first-line treatment combination for patients with pleural mesothelioma. Nivolumab-ipilimumab improved the survival, however, 30.3% of the patients suffered from grade 3-4 treatment related adverse events (TRAE's) and TRAE's led to discontinuation in 23.0% of all patients. Here, we present the first real-world data of nivolumab plus ipilimumab in patients with malignant mesothelioma treated in two mesothelioma expert centers., Methods: Clinical data of patients with mesothelioma treated with nivolumab and ipilimumab were prospectively collected. Clinical parameters were obtained every visit, CT scans were evaluated every 12 weeks and adverse events were assessed continuously during the treatment. Data on grade 2-5 TRAE's and activity (overall response rate (ORR), duration of response (DOR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS) were reported., Results: Between January 2021 and August 2022, 184 patients were treated with nivolumab plus ipilimumab. The median follow-up was 12.1 months (95 %CI 11.1 - 13.1). Grade 3-4 TRAEs were seen in 27.7 % of the patients and 25.0 % discontinued immunotherapy treatment early because of TRAE's. ORR was 21.7 % (95 % CI 15.7-27.7), median DOR was 5.7 months (IQR 3.2-8.7) and DCR at 12 weeks 56.0 % (95 % CI 48.8-63.2). The mPFS was 5.5 months (95 %CI 4.1-6.9), mOS was 14.1 months (95 % CI 11.1-18.2)., Conclusions: Nivolumab plus ipilimumab had an equal efficacy in a real-world comparable population but also a high risk of TRAE's, leading to discontinuation of treatment in 25% of the patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Checkpoint inhibitor (CI) therapy has revolutionized treatment for non-small cell lung cancer (NSCLC). However, a proportion of patients do not respond to CI therapy for unknown reasons. Although the current paradigm in anti-tumor immunity evolves around T cells, the presence of tertiary lymphoid structures and memory B cells has been positively correlated with response to CI therapy in NSCLC. In addition, double negative (DN) (CD27 - IgD - ) B cells have been shown to be abundant in NSCLC compared to healthy lung tissue and inversely correlate with the intratumoral presence of memory B cells. Nonetheless, no study has correlated DN B cells to survival in NSCLC., Methods: In this study, we evaluated the presence and phenotype of B cells in peripheral blood with flow cytometry of patients with NSCLC and mesothelioma before receiving CI therapy and correlated these with clinical outcome., Results: Non-responding patients showed decreased frequencies of B cells, yet increased frequencies of antigen-experienced CD21- DN (Atypical) B cells compared to responding patients and HC, which was confirmed in patients with mesothelioma treated with CI therapy., Conclusions: These data show that the frequency of CD21- DN B cells correlates with lack of response to CI therapy in thoracic malignancies. The mechanism by which CD21- DN B cells hamper CI therapy remains unknown. Our findings support the hypothesis that CD21- DN B cells resemble phenotypically identical exhausted B cells that are seen in chronic infection or function as antigen presenting cells that induce regulatory T cells., Competing Interests: Declaration of Competing Interest Daphne Dumoulin reports personal fees from Roche, BMS, MSD, Pfizer, Astra Zeneca and Novartis outside the submitted work. Joachim Aerts reports personal fees and nonfinancial support from MSD, personal fees from BMS, Boehringer Ingelheim, Amphera, Eli-Lilly, Takeda, Bayer, Roche, Astra Zeneca outside the submitted work; in addition, Joachim Aerts has a patent allogenic tumor cell lysate licensed to Amphera, a patent combination immunotherapy in cancer pending, and a patent biomarker for immunotherapy pending; Joachim Aerts served as an unpaid editorial board member of Translational Lung Cancer Research from September 2019 to September 2021. The other authors do not have a conflict of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Peritoneal mesothelioma (PeM) is a rare malignancy with a poor prognosis. Currently there is a lack of effective systemic therapies. Due to the rarity of PeM, it is challenging to study new treatment options. Off-label use of targeted drugs could be an effective approach. This scoping review aims to explore the genomic landscape of PeM to identify potential therapeutic targets., Materials and Methods: A systematic literature search of Embase, Medline, Web of Science, the Cochrane Library, and Google Scholar was carried out up to 1 November 2022. Studies that reported on molecular alterations in PeM detected by high-throughput sequencing techniques were included. Genes that were altered in ≥1% of PeMs were selected for the identification of potential targeted therapies., Results: Thirteen articles were included, comprising 824 PeM patients. In total, 142 genes were altered in ≥1% of patients, of which 7 genes were altered in ≥10%. BAP1 was the most commonly altered gene (50%). Other commonly altered genes were NF2 (25%), CDKN2A (23%), CDKN2B (17%), PBRM1 (15%), TP53 (14%), and SETD2 (13%). In total, 17% of PeM patients were carriers of a germline mutation, mainly in BAP1 (7%)., Conclusions: This scoping review provides an overview of the mutational landscape of PeM. Germline mutations might be a larger contributor to the incidence of PeM than previously thought. Currently available targeted therapy options are limited, but several targeted agents [such as poly (ADP-ribose) polymerase (PARP), enhancer of zeste homolog 2 (EZH2), and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors] were identified that might provide new targeted therapy options in the future., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Tumor-associated macrophages (TAMs) can be abundantly present in numerous cancer types. Under influence of various stimuli in the tumor microenvironment TAMs develop into a tumor-inhibitory (M1) or tumor-promoting (M2) phenotype. Recently, the role of TAMs in tumor biology and their prognostic value in cancer has become a major topic of interest. In this review we will discuss the importance of TAMs in the pathogenesis and clinical outcome of lung cancer and mesothelioma patients. In addition, the potential of TAMs as therapeutic targets will be discussed., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Treatment options for malignant mesothelioma are limited, and the results with conventional therapies have been rather disappointing to this date. Chemotherapy is the only evidence-based treatment for mesothelioma patients in good clinical condition, with an increase in median survival of only 2 months. Therefore, there is urgent need for a different approach to battle this malignancy. As chronic inflammation precedes mesothelioma, the immune system plays a key role in the initiation of this type of tumour. Also, many immunological cell types can be found within the tumour at different stages of the disease. However, mesothelioma cells can evade the surveillance capacity of the immune system. They build a protective tumour microenvironment to harness themselves against the immune system's attacks, in which they even abuse immune cells to act against the antitumour immune response. In our opinion, modulating the immune system simultaneously with the targeting of mesothelioma tumour cells might prove to be a superior treatment. However, this strategy is challenging since the tumour microenvironment possesses numerous forms of defence strategies. In this paper, we will discuss the interplay between immunological cells that can either inhibit or stimulate tumour growth and the challenges associated with immunotherapy. We will provide possible strategies and discuss opportunities to overcome these problems.

Background: Suppressive immune cells present in tumour microenvironments are known to augment tumour growth and hamper efficacy of antitumour therapies. The amino-bisphosphonate Zoledronic acid (ZA) is considered as an antitumour agent, as recent studies showed that ZA prolongs disease-free survival in cancer patients. The exact mechanism is a topic of debate; it has been suggested that ZA targets tumour-associated macrophages (TAMs)., Methods: We investigate the role of ZA on the myeloid differentiation to TAMs in murine mesothelioma in vivo and in vitro. Mice were intraperitoneally inoculated with a lethal dose of mesothelioma tumour cells and treated with ZA to determine the effects on myeloid differentiation and survival., Results: We show that ZA impaired myeloid differentiation. Inhibition of myeloid differentiation led to a reduction in TAMs, but the number of immature myeloid cells with myeloid-derived suppressor cell (MDSC) characteristics was increased. In addition, ZA affects the phenotype of macrophages leading to reduced level of TAM-associated cytokines in the tumour microenvironment. No improvement of survival was observed., Conclusion: We conclude that ZA leads to a reduction in macrophages and impairs polarisation towards an M2 phenotype, but this was associated with an increase in the number of immature myeloid cells, which might diminish the effects of ZA on survival.

The aim of the study was to establish in a prospective and blinded manner the diagnostic yield of morphology, immunocytochemistry (ICH) and electron microscopy (EM) in the cytological analysis of malignant pleural mesothelioma (MPM). Pleural fluid from consecutive patients, 14 with a histologically proven MPM, 12 with a malignant pleuritis due to adenocarcinoma (AC), and 13 with a reactive pleural effusion (RM), was separately analyzed. Smears were incubated with monoclonal antibodies (Tag72, Ber-Ep4, anti-CEA, EMA). These were considered suggestive for MPM when only EMA stained positive, for AC when three out of four markers stained positive, and for RM when no marker stained positive. The post-test probability of the morphological, ICH, and EM analysis were 92, 100, 92% or MPM, 91, 100, 86% for AC, and 88, 88, 90% for RM, respectively. We concluded that the high post-test probability of a combined morphological and ICH diagnosis of MPM warrants to cease further diagnostic procedures in these patients. Electron microscopy did not add to accuracy of diagnosis., ((c) 2006 Wiley-Liss, Inc.)