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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.)

Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict responses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4 + and CD8 + T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8 + T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Malignant mesothelioma (MM) is an aggressive cancer that primarily arises from the pleura (MPM) or peritoneum (MPeM), mostly due to asbestos exposure. This study reviewed the Dutch population-based incidence, treatment and survival since the national ban on asbestos in 1993., Materials and Methods: Patients with MPM or MPeM diagnosed from 1993 to 2018 were selected from the Dutch cancer registry. Annual percentage change (APC) was calculated for (age-specific and sex-specific) revised European standardised incidence rates (RESR). Treatment pattern and Kaplan-Meier overall survival analyses were performed., Results: In total, 12 168 patients were included in the study. For male patients younger than 80 years, the MM incidence significantly decreased in the last decade (APC ranging between -9.4% and -1.8%, p<0.01). Among both male and female patients aged over 80 years, the incidence significantly increased during the entire study period (APC 3.3% and 4.6%, respectively, p<0.01). From 2003 onwards, the use of systemic chemotherapy increased especially for MPM (from 9.3% to 39.4%). Overall, 62.2% of patients received no antitumour treatment. The most common reasons for not undergoing antitumour treatment were patient preference (42%) and performance status (25.6%). The median overall survival improved from 7.3 (1993-2003) to 8.9 (2004-2011) and 9.3 months from 2012 to 2018 (p<0.001)., Conclusion: The peak of MM incidence was reached around 2010 in the Netherlands, and currently the incidence is declining in most age groups. The use of systemic chemotherapy increased from 2003, which likely resulted in improved overall survival over time. The majority of patients do not receive treatment though and prognosis is still poor., Competing Interests: Competing interests: JAB reports reimbursements for his institution (Netherlands Cancer Institute) outside the submitted work from Roche, AstraZeneca and Boehringer Ingelheim. JA reports grants from Amphera, grants from Roche, ownership interest (including patents) from Amphera, and advisory roles for Amphera, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, MSD and Roche, outside the submitted work. PB reports financial support to his institution (Netherlands Cancer Institute) for studies by Bristol Myers Squibb and Merck, and advisory roles for Bristol Myers Squibb, Merck and BeiGene. RC reports personal speakers fees from Roche, Pfizer and Bristol Myers Squibb, and personal advisory fees from MSD and Roche, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The role of surgery for early stage malignant pleural mesothelioma (MPM) remains controversial. Current expert opinion is only to treat patients surgically as part of multimodality therapy. It is still challenging to identify patients who will not benefit from surgery. We specifically evaluated tumor-related parameters in combination with clinical parameters to identify prognostic markers for survival., Methods: Clinical data of 27 consecutive patients with MPM treated with extended pleurectomy and decortication within a multimodality approach were collected and analyzed. Several tumor (immuno-)histopathologic characteristics were determined on resected tumor material, among which MTAP and Ki67 (MIB-1). Univariable and multivariable analyses served to correlate clinical and tumor-related parameters to overall survival (OS) and progression-free survival (PFS)., Results: The median PFS (mPFS) was 15.3, and the median OS (mOS) was 26.5 months. Patients with a Ki67 score greater than 10% had a significantly shorter PFS (mPFS = 8.81 versus 25.35 mo, p  = 0.001) and OS (mOS 19.7 versus 44.5 mo, p  = 0.002) than those with a Ki67 score less than or equal to 10. Receiver operating characteristic curve analysis for Ki67 revealed an area under the curve of 0.756 with a sensitivity of 90% and specificity of 71% for a cutoff of 10% for Ki67. Patients with loss of MTAP had a significantly shorter mPFS (9 versus 21.1 mo, p  = 0.014) and mOS (19.7 versus 42.6 mo, p  = 0.047) than those without MTAP loss., Conclusions: In our study, Ki67 was prognostic for OS and PFS in patients with MPM treated with extended pleurectomy/decortication in a multimodality approach. Determination of Ki67 before surgery combined with specific clinical parameters could assist in clinical decision making by identifying patients, with high Ki67, who are unlikely to benefit from surgery., (© 2021 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer.)

Background: In preclinical models, statins showed vaccine adjuvant activities and synergized with PD-1 inhibitors. We analyzed the impact of statin treatment on clinical outcome in thoracic cancer patients treated with PD-1 inhibitors., Methods: A total of 82 malignant pleural mesothelioma (MPM) and 179 advanced non-small cell lung cancer (aNSCLC) patients treated with PD-1 inhibitors as second or further line treatment were examined. Seventy-seven MPM patients treated with standard chemotherapy were analyzed as control cohort. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were calculated., Results: Among 253 patients with available data, statin use was associated with increased ORR (32% versus 18%, P = .02), PFS (median 6.7 versus 2.9 months, hazard ratio [HR] 0.57, 95% CI 0.39-0.83, P < .01), and OS (median 13.1 versus 8.7 months, HR 0.67, 95% CI 0.45-1.00, P = .05). In the control MPM cohort treated with chemotherapy (n = 77), no association was found. MPM patients who used statins showed improved ORR (22% versus 6%, P = .05), PFS (median 6.7 versus 2.4 months, P < .01), and OS (median not reached versus 6.0 months, P = .01). In aNSCLC patients, statin use was associated with improved ORR (40% versus 22%, P = .04) and PFS (median 7.8 versus 3.6 months, P = .03), but no significant difference in OS was found (median 13.1 versus 10.1 months, P = .30). Multivariable analysis confirmed the correlation between statin use and better PFS and OS in MPM and better PFS in aNSCLC. In the whole cohort, high but not low/moderate-intensity statins were associated with better OS compared to no user (P = .02 and P = .59, respectively)., Conclusions: Our study showed that statins are associated with better clinical outcome in MPM and aNSCLC patients treated with PD-1 inhibitors in an intensity-dependent manner., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Relevant financial activities outside the submitted work: DD reports receiving speakers fee from BMS, Roche, Pfizer, and Novartis. RC reports consulting for Roche, MSD, Boehringer Ingelheim and receiving speakers fee from BMS, Roche, Pfizer, Boehringer Ingelheim, Novartis. JA reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV, and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, MSD, Takeda, Bayer, Astra Zeneca and Roche. RB is a consultant/advisory board member for Astra Zeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli-Lilly, Roche. The other authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%., Patients and Methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes., Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival., Conclusions: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%., Methods: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%., Results: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis., Conclusion: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.

Background: Randomized phase III trials are ongoing to investigate the efficacy of nivolumab in malignant pleural mesothelioma (MPM), but real-world data are still scarce. In this real-world study, we investigated the clinical outcomes of nivolumab treatment in pre-treated MPM patients., Methods: Data from 107 nivolumab treated MPM patients within the Dutch expanded access program were retrospectively analyzed. Treatment was independent of programmed death ligand 1 (PD-L1) expression on tumor samples. Univariable and multivariable analyses were performed to evaluate the relationship between clinically important factors, baseline peripheral blood parameters and survival. The landmark method was used to compare the outcome of patients according to their radiological response., Results: In the full cohort, the median progression-free survival (mPFS) was 2.3 months (95% CI: 1.6-2.9) and the median overall survival (mOS) was 6.7 months (95% CI: 6.2-10.0). After 12 weeks, the disease control rate (DCR) was 37% and the objective response rate (ORR) was 10%. PD-L1 status was determined in 33 patients (30%) and PD-L1 positivity (≥1%) was associated with an improved ORR (36% vs. 9%, P value 0.05), but not with PFS or OS. Low albumin was associated with worse OS (P value 0.002). Median OS was significantly longer for patients who had partial response to treatment (P value 0.0002)., Conclusions: In this real-world analysis, ORR and mOS were lower compared to those obtained in phase II trials. However, exceptional survival rates were observed in patients who had a radiological response. Although we cannot determine whether prognostic or predictive, PD-L1 expression and albumin were associated with greater response rate and may represent useful biomarkers for nivolumab treatment in MPM., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-19-686). DWD reports personal fees from Roche, BMS, MSD, Pfizer, Astra Zeneca and Novartis outside the submitted work. RC reports speakers fee from Roche, Pfizer and BMS, personal fees from Advisory Board MSD and Advisory Board Roche outside the submitted work. JAB reports other from Bristol-Meyers Squibb, MSD B.V., F. Hoffmann- La Roche Ltd. during the conduct of the study. PB reports other from Bristol-Myers Squibb, MSD B.V., AstraZeneca, Takeda outside the submitted work. JGJVA reports personal fees and non-financial support from MSD, personal fees from BMS, Boehringer Ingelheim, Amphera, Eli-Lilly, Takeda, Bayer, Roche, Astra Zeneca outside the submitted work; in addition, JGJVA has a patent allogenic tumor cell lysate licensed to Amphera, a patent combination immunotherapy in cancer pending, and a patent biomarker for immunotherapy pending; JGJVA serves as an unpaid editorial board member of Translational Lung Cancer Research from Sep 2019 to Sep 2021. The other authors have no conflicts of interest to declare. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (2020 Translational Lung Cancer Research. All rights reserved.)

Malignant pleural mesothelioma (MPM) is a treatment recalcitrant tumor with a poor overall survival (OS). Current approved treatment consists of first line chemotherapy that only modestly increases OS, illustrating the desperate need for other treatment options in MPM. Unfortunately, clinical studies that investigate the effectivity of checkpoint inhibitor (CI) treatment failed to improve clinical outcome over current applied therapies. In general, MPM is characterized as an immunological cold tumor with low T-cell infiltration, which could explain the disappointing results of clinical trials investigating CI treatment in MPM. Currently, many other therapeutic approaches, such as cellular therapies and cancer vaccines are investigated that could induce a tumor-specific immune response and increase of the number of tumor-infiltrating lymphocytes. In this review we will discuss these novel treatment approaches for MPM., (Copyright © 2020 Belderbos, Vroman and Aerts.)

Background: Malignant pleural mesothelioma (MPM) is a highly lethal malignancy in need for new treatment options. Although immunotherapies have been shown to boost a tumor-specific immune response, not all patients respond and prognostic biomarkers are scarce. In this study, we determined the peripheral blood T cell receptor β (TCRβ) chain repertoire of nine MPM patients before and 5 weeks after the start of dendritic cell (DC)-based immunotherapy., Materials and Methods: We separately profiled PD1 + and PD1 - CD4 + and CD8 + T cells, as well as Tregs and analyzed 70 000 TCRβ sequences per patient., Results: Strikingly, limited TCRβ repertoire diversity and high average clone sizes in total CD3 + T cells before the start of immunotherapy were associated with a better clinical response. To explore the differences in TCRβ repertoire prior-DC-therapy and post-DC-therapy, for each patient the TCRβ clones present in the total CD3 + T cell fractions were classified into five categories, based on therapy-associated frequency changes: expanding, decreasing, stable, newly appearing and disappearing clones. Subsequently, the presence of these five groups of clones was analyzed in the individual sorted T cell fractions. DC-therapy primarily induced TCRβ repertoire changes in the PD1 + CD4 + and PD1 + CD8 + T cell fractions. In particular, in the PD1 + CD8 + T cell subpopulation we found high frequencies of expanding, decreasing and newly appearing clones. Conversion from a PD1 - to a PD1 + phenotype was significantly more frequent in CD8 + T cells than in CD4 + T cells. Hereby, the number of expanding PD1 + CD8 + T cell clones-and not expanding PD1 + CD4 + T cell clones following immunotherapy positively correlated with overall survival, progression-free survival and reduction of tumor volume., Conclusion: We conclude that the clinical response to DC-mediated immunotherapy is dependent on both the pre-existing TCRβ repertoire of total CD3 + T cells and on therapy-induced changes, in particular expanding PD1 + CD8 + T cell clones. Therefore, TCRβ repertoire profiling in sorted T cell subsets could serve as predictive biomarker for the selection of MPM patients that benefit from immunotherapy., Trial Registration Number: NCT02395679., Competing Interests: Competing interests: JGJVA reports receiving commercial grants from Amphera, holds ownership interests (including patents) in Amphera BV, and is a consultant/advisory board member for Amphera., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Malignant pleural mesothelioma (MPM) is an aggressive, treatment resistant neoplasm. The current treatment, consisting of antifolate and platinum-based chemotherapy, improves the median overall survival with only 3 months. Adjuvant bevacizumab generates an additional 2 months survival benefit. Checkpoint inhibitors (CI) have shown promising clinical effects in only a minority of patients. A possible reason is that MPM patients have low numbers of tumor-infiltrating CD8 + T-cells. Dendritic cell (DC) therapy can induce an immune response and activate tumor-specific CD8 + T-cells. Allogeneic mesothelioma tumor-lysate loaded DC therapy has proven effective in mice and safe and feasible in humans. We have designed a randomized, phase II/III, multicenter, open-label trial to examine the efficacy of DC therapy in humans with histologically proven MPM., Methods: In this open-label, multicenter, randomized phase II/III trial patients will be randomized to receive either DC therapy plus best supportive care (BSC) or BSC alone according to the discretion of the local investigator after first line chemotherapy treatment. The primary end point will be overall survival. The secondary endpoints will be safety and tolerability, progression-free survival, overall response rate and quality of life., Discussion: This phase II/III trial will determine whether DC therapy in patients with MPM is safe and effective as a maintenance treatment and subsequently might be a new treatment option for MPM., Competing Interests: Conflicts of Interest: JGJV Aerts reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV, and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, MSD, Takeda, Bayer en Astra-Zeneca and Roche. R. Cornelissen reports consulting for Roche, MSD, Boehringer Ingelheim and receiving speakers fee from BMS, Roche, Pfizer, Boehringer Ingelheim, Novartis. P. Baas reports receiving advisorships from Merck and BMS. The other authors have no conflicts of interest to declare.

Dendritic cells (DCs) are the most potent antigen-presenting cells and are the key initiator of tumor-specific immune responses. These characteristics are exploited by DC therapy, where DCs are ex vivo loaded with tumor-associated antigens (TAAs) and used to induce tumor-specific immune responses. Unfortunately, clinical responses remain limited to a proportion of the patients. Tumor characteristics and the immunosuppressive tumor microenvironment (TME) of the tumor are likely hampering efficacy of DC therapy. Therefore, reducing the immunosuppressive TME by combining DC therapy with other treatments could be a promising strategy. Initially, conventional cancer therapies, such as chemotherapy and radiotherapy, were thought to specifically target cancerous cells. Recent insights indicate that these therapies additionally augment tumor immunity by targeting immunosuppressive cell subsets in the TME, inducing immunogenic cell death (ICD), or blocking inhibitory molecules. Therefore, combining DC therapy with registered therapies such as chemotherapy, radiotherapy, or checkpoint inhibitors could be a promising treatment strategy to improve the efficacy of DC therapy. In this review, we evaluate various clinical applicable combination strategies to improve the efficacy of DC therapy.