Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with limited therapy options and dismal prognosis. In recent years, the role of immune cells within the tumor microenvironment (TME) ...has become a major area of interest. In this review, we discuss the current knowledge of heterogeneity in immune cell content and checkpoint expression in MPM in relation to prognosis and prediction of treatment efficacy. Generally, immune-suppressive cells such as M2 macrophages, myeloid-derived suppressor cells and regulatory T cells are present within the TME, with extensive heterogeneity in cell numbers. Infiltration of effector cells such as cytotoxic T cells, natural killer cells and T helper cells is commonly found, also with substantial patient to patient heterogeneity. PD-L1 expression also varied greatly (16-65%). The infiltration of immune cells in tumor and associated stroma holds key prognostic and predictive implications. As such, there is a strong rationale for thoroughly mapping the TME to better target therapy in mesothelioma. Researchers should be aware of the extensive possibilities that exist for a tumor to evade the cytotoxic killing from the immune system. Therefore, no "one size fits all" treatment is likely to be found and focus should lie on the heterogeneity of the tumors and TME.
The tumor micro-environment and especially the different macrophage phenotypes appear to be of great influence on the behavior of multiple tumor types. M1 skewed macrophages possess anti-tumoral ...capacities, while the M2 polarized macrophages have pro-tumoral capacities. We analyzed if the macrophage count and the M2 to total macrophage ratio is a discriminative marker for outcome after surgery in malignant pleural mesothelioma (MPM) and studied the prognostic value of these immunological cells.
8 MPM patients who received induction chemotherapy and surgical treatment were matched on age, sex, tumor histology, TNM stage and EORTC score with 8 patients who received chemotherapy only. CD8 positive T-cells and the total macrophage count, using the CD68 pan-macrophage marker, and CD163 positive M2 macrophage count were determined in tumor specimens prior to treatment.
The number of CD68 and CD163 cells was comparable between the surgery and the non-surgery group, and was not related to overall survival (OS) in both the surgery and non-surgery group. However, the CD163/CD68 ratio did correlate with OS in both in the total patient group (Pearson r -0.72, p<0.05). No correlation between the number of CD8 cells and prognosis was found.
The total number of macrophages in tumor tissue did not correlate with OS in both groups, however, the CD163/CD68 ratio correlates with OS in the total patient group. Our data revealed that the CD163/CD68 ratio is a potential prognostic marker in epithelioid mesothelioma patients independent of treatment but cannot be used as a predictive marker for outcome after surgery.
Immune checkpoint inhibitors (ICI) have become the standard of care treatment for several tumor types. ICI-induced pneumonitis is a serious complication seen with treatment with these agents. Cancer ...has been reported to be one of the risk factors for severe coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that has engulfed the world in the last couple of months. In patients with cancer treated with ICI who present at the emergency department with respiratory symptoms during the COVID-19 pandemic, correct diagnosis can be challenging. Symptoms and radiological features of ICI pneumonitis can be overlapping with those of COVID-19 related pneumonia. For the latter, dexamethasone and remdesivir have shown encouraging results, while vaccines are currently being evaluated in phase III trials. The mainstay of treatment in ICI pneumonitis is immunosuppressive therapy, as this is a potentially fatal adverse event. It has been speculated that immunosuppression may be associated with increased risk of progression to severe COVID-19, especially during the early stage of infection with SARS-CoV-2. Therefore, distinction between these two entities is warranted. We summarize the clinical, radiological features as well as additional investigations of both entities, and suggest a diagnostic algorithm for distinction between the two. This algorithm may be a supportive tool for clinicians to diagnose the underlying cause of the pneumonitis in patients treated with ICI during this COVID-19 pandemic.
Prognostication tools for early-stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT) are currently lacking. The purpose of this study was to develop ...and externally validate a nomogram to predict overall survival in individual patients with peripheral early-stage disease.
A total of 587 NSCLC patients treated with biologically effective dose > 100 Gy
were eligible. A Cox proportional hazards model was used to build a nomogram to predict 6-month, 1-year, 3-year and 5-year overall survival. Internal validation was performed using bootstrap sampling. External validation was performed in a separate cohort of 124 NSCLC patients with central tumors treated with SBRT. Discriminatory ability was measured by the concordance index (C-index) while predictive accuracy was assessed with calibration slope and plots.
The resulting nomogram was based on six prognostic factors: age, sex, Karnofsky Performance Status, operability, Charlson Comorbidity Index, and tumor diameter. The slope of the calibration curve for nomogram-predicted versus Kaplan-Meier-estimated overall survival was 0.77. The C-index of the nomogram (corrected for optimism) was moderate at 0.64. In the external validation cohort, the model yielded a C-index of 0.62.
We established and validated a nomogram which can provide individual survival predictions for patients with early stage lung cancer treated with SBRT. The nomogram may assist patients and clinicians with treatment decision-making.
Lung cancer is the leading cause of cancer death in Europe. Screening by means of low-dose computed tomography (LDCT) can shift detection to an earlier stage and reduce lung cancer mortality in ...high-risk individuals. However, to date, Poland, Croatia, Italy, and Romania are the only European countries to commit to large-scale implementation of targeted LDCT screening. Using a health systems approach, this article evaluates key factors needed to enable the successful implementation of screening programs across Europe. Recent literature on LDCT screening was reviewed for 10 countries (Belgium, Croatia, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, and United Kingdom) and complemented by 17 semistructured interviews with local experts. Research findings were mapped against a health systems framework adapted for lung cancer screening. The European policy landscape is highly variable, but potential barriers to implementation are similar across countries and consistent with those reported for other cancer screening programs. While consistent quality and safety of screening must be ensured across all screening centers, system factors are also important. These include appropriate data infrastructure, targeted recruitment methods that ensure equity in participation, sufficient capacity and workforce training, full integration of screening with multidisciplinary care pathways, and smoking cessation programs. Stigma and underlying perceptions of lung cancer as a self-inflicted condition are also important considerations. Building on decades of implementation research, governments now have a unique opportunity to establish effective, efficient, and equitable lung cancer screening programs adapted to their health systems, curbing the impact of lung cancer on their populations.
Background
Improved outcome in tobacco smoking patients with non‐small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this ...association during first‐line immunotherapy in patients with high PD‐L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts.
Methods
We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first‐line pembrolizumab and platinum‐based chemotherapy.
Results
A total of 962 NSCLC patients with PD‐L1 expression ≥50% who received first‐line pembrolizumab and 462 NSCLC patients who received first‐line platinum‐based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio HR = 1.49 95% CI: 1.15–1.92, p = 0.0022) and death (HR = 1.38 95% CI: 1.02–1.87, p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 95% CI: 0.52–1.05, p = 0.1003) and death (HR = 0.67 95% CI: 0.45–1.01, p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case–control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression‐free survival (PFS) (HR = 1.68 95% CI: 1.17–2.40, p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 95% CI: 0.84–2.07, p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 95% CI: 0.49–0.95, p = 0.0255) and OS (HR = 0.66 95% CI: 0.45–0.97, p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts.
Conclusions
Among metastatic NSCLC patients with PD‐L1 expression ≥50% receiving first‐line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first‐line chemotherapy.
Improved outcome in tobacco smoking NSCLC patients following treatment with immune checkpoint inhibitors (ICIs) has previously been reported. Little is known regarding this association during first‐line immunotherapy in patients with high PD‐L1 expression. Clinical outcomes according to the smoking status of two large multicenter cohorts were compared in this study. Smokers with high PD‐L1 expression ≥ 50% experienced improved progression‐free survival (PFS) and overall survival (OS) with first‐line pembrolizumab. The opposite trend was found in NSCLC patients treated with first‐line platinum‐based chemotherapy.
Rationale: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor ...lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tolerated treatment in malignant pleural mesothelioma patients and further as a method to reduce circulating Tregs.
Objectives: The aim of this study was to establish the immunological effects of mCTX alone and in combination with DC-based immunotherapy on circulating Treg and other T cell subsets in mesothelioma patients.
Methods: Ten patients received mCTX and DC-based immunotherapy after chemotherapy (n = 5) or chemotherapy and debulking surgery (n = 5). Peripheral blood mononuclear cells before, during and after treatment were analyzed for various Treg and other lymphocyte subsets by flow cytometry.
Results: After one week treatment with mCTX, both activated FoxP3
hi
and naïve CD45RA
+
Tregs were effectively decreased in all patients. In addition, a shift from naïve and central memory towards effector memory and effector T cells was observed. Survival analysis showed that overall Treg levels before treatment were not correlated with survival, however, nTreg levels before treatment were positively correlated with survival. After completion of mCTX and DC-based immunotherapy treatment, all cell subsets returned to baseline levels, except for the proportions of proliferating EM CD8 T cells, which increased.
Conclusions: mCTX treatment effectively reduced the proportions of circulating Tregs, both aTregs and nTregs, thereby favoring EM T cell subsets in mesothelioma patients. Interestingly, baseline levels of nTregs were positively correlated to overall survival upon complete treatment.
Background: Malignant pleural mesothelioma (MPM) is a fatal neoplasm with, if untreated, poor survival of approximately nine months from diagnosis. Until recently, phase II–III immunotherapy trials ...did not show any significant benefit. The lack of immunotherapy efficacy can be explained by the fact that mesothelioma is a tumor with an “immune desert” phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of DCs, which were ex-vivo cultured, exposed to (tumor-associated) antigens, and subsequently activated, this “immune desert” phenotype might be turned into an “inflamed” phenotype. Three phase I/II studies have been performed and published using activated DCs, which support this concept. We here report on the long-term survival of patients treated with DCs in three phase I/II studies. Methods: Survival data of the phase I/II trials using DC therapy in MPM patients were obtained and subsequently analyzed. In the first two trials, DCs were loaded with autologous tumor lysate. In the third trial, DCs were loaded with allogeneic mesothelioma tumor cell line lysate. Results: In the three studies combined, 29 patients with MPM were treated with DC vaccination between 2006 and 2015. At data cut-off, the median OS was 27 months (95% CI: 21–47 months). OS at 2 years was 55.2% (95% CI: 39.7–76.6%), and OS at 5 years was 20.7% (95% CI: 10.1–42.2%). Conclusions: The long-term survival of DC therapy in MPM in these three trials is promising, which is the basis for the randomized phase II/III DENIM study. This DENIM study is currently enrolling, and the results of which have to be awaited for definite conclusions.
Highlights • Pleural effusion composition is dynamic and influenced by treatment. • The immune infiltrate in the tumor is not necessarily mimicked in the pleural effusion. • Pleural effusion provides ...a dynamic insight in the tumor-host interactions.
BackgroundMalignant 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 methodsWe separately profiled PD1+ and PD1−CD4+ and CD8+ T cells, as well as Tregs and analyzed 70 000 TCRβ sequences per patient.ResultsStrikingly, 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.ConclusionWe 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 numberNCT02395679.
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