Immune checkpoint inhibitors (ICIs) have provided tremendous clinical benefit in several cancer types. However, systemic activation of the immune system also leads to several immune-related adverse ...events. Of these, ICI-mediated colitis (IMC) occurs frequently and is the one with the highest absolute fatality. To improve current treatment strategies, it is important to understand the cellular mechanisms that induce this form of colitis. In this review, we discuss important pathways that are altered in IMC in mouse models and in human colon biopsy samples. This reveals a complex interplay between several types of immune cells and the gut microbiome. In addition to a mechanistic understanding, patients at risk should be identifiable before ICI therapy. Here we propose to focus on T-cell subsets that interact with bacteria after inducing epithelial damage. Especially, intestinal resident immune cells are of interest. This may lead to a better understanding of IMC and provides opportunities for prevention and management.
Programmed cell death ligand 1 (PD‐L1) immunohistochemistry is used to determine which patients with advanced non‐small‐cell lung cancer (NSCLC) respond best to treatment with PD‐L1 inhibitors. For ...each inhibitor, a unique immunohistochemical assay was developed. This systematic review gives an up‐to‐date insight into the comparability of standardised immunohistochemical assays and laboratory‐developed tests (LDTs), focusing specifically on tumour cell (TC) staining and scoring. A systematic search was performed identifying publications that assessed interassay, interobserver and/or interlaboratory concordance of PD‐L1 assays and LDTs in tissue of NSCLC patients. Of 4294 publications identified through the systematic search, 27 fulfilled the inclusion criteria and were of sufficient methodological quality. Studies assessing interassay concordance found high agreement between assays 22C3, 28‐8 and SP263 and properly validated LDTs, and lower concordance for comparisons involving SP142. A decrease in concordance, however, is seen with use of cut‐offs, which hampers interchangeability of PD‐L1 immunohistochemistry assays and LDTs. Studies assessing interobserver concordance found high agreement for all assays and LDTs, but lower agreement with use of a 1% cut‐off. This may be problematic in clinical practice, as discordance between pathologists at this cut‐off may result in some patients being denied valuable treatment options. Finally, five studies assessed interlaboratory concordance and found moderate to high agreement levels for various assays and LDTs. However, to assess the actual existence of interlaboratory variation in PD‐L1 testing and PD‐L1 positivity in clinical practice, studies using real‐world clinical pathology data are needed.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: There are no specifically approved targeted therapies for the most common genomically defined subset of non–small cell lung cancer (NSCLC), KRAS-mutant lung cancer. OBJECTIVE: To compare ...efficacy of the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib + docetaxel with docetaxel alone as a second-line therapy for advanced KRAS-mutant NSCLC. DESIGN, SETTING, AND PARTICIPANTS: Multinational, randomized clinical trial conducted at 202 sites across 25 countries from October 2013 through January 2016. Of 3323 patients with advanced NSCLC and disease progression following first-line anticancer therapy tested for a KRAS mutation, 866 were enrolled and 510 randomized. Primary reason for exclusion was ineligibility. The data cutoff date for analysis was June 7, 2016. INTERVENTIONS: Patients were randomized 1:1; 254 to receive selumetinib + docetaxel and 256 to receive placebo + docetaxel. MAIN OUTCOMES AND MEASURES: Primary end point was investigator assessed progression-free survival. Secondary end points included overall survival, objective response rate, duration of response, effects on disease-related symptoms, safety, and tolerability. RESULTS: Of 510 randomized patients (mean age, 61.4 years SD, 8.3; women, 207 41%), 505 patients (99%) received treatment and completed the study (251 received selumetinib + docetaxel; 254 received placebo + docetaxel). At the time of data cutoff, 447 patients (88%) had experienced a progression event and 346 deaths (68%) had occurred. Median progression-free survival was 3.9 months (interquartile range IQR, 1.5-5.9) with selumetinib + docetaxel and 2.8 months (IQR, 1.4-5.5) with placebo + docetaxel (difference, 1.1 months; hazard ratio HR, 0.93 95% CI, 0.77-1.12; P = .44). Median overall survival was 8.7 months (IQR, 3.6-16.8) with selumetinib + docetaxel and 7.9 months (IQR, 3.8-20.1) with placebo + docetaxel (difference, 0.9 months; HR, 1.05 95% CI, 0.85-1.30; P = .64). Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel (difference, 6.4%; odds ratio, 1.61 95% CI, 1.00-2.62; P = .05). Median duration of response was 2.9 months (IQR, 1.7-4.8; 95% CI, 2.7-4.1) with selumetinib + docetaxel and 4.5 months (IQR, 2.3-7.3; 95% CI, 2.8-5.6) with placebo + docetaxel. Adverse events of grade 3 or higher were more frequent with selumetinib + docetaxel (169 adverse events 67% for selumetinib + docetaxel vs 115 adverse events 45% for placebo + docetaxel; difference, 22%). CONCLUSIONS AND RELEVANCE: Among patients with previously treated advanced KRAS-mutant non–small cell lung cancer, addition of selumetinib to docetaxel did not improve progression-free survival compared with docetaxel alone. TRIAL REGISTRATION: clinicaltrials.gov: NCT01933932
Dendritic cells (DCs) are essential in antitumor immunity. In humans, three main DC subsets are defined: two types of conventional DCs (cDC1s and cDC2s) and plasmacytoid DCs (pDCs). To study DC ...subsets in the tumor microenvironment (TME), it is important to correctly identify them in tumor tissues. Tumor‐derived DCs are often analyzed in cell suspensions in which spatial information about DCs which can be important to determine their function within the TME is lost. Therefore, we developed the first standardized and optimized multiplex immunohistochemistry panel, simultaneously detecting cDC1s, cDC2s, and pDCs within their tissue context. We report on this panel's development, validation, and quantitative analysis. A multiplex immunohistochemistry panel consisting of CD1c, CD303, X‐C motif chemokine receptor 1, CD14, CD19, a tumor marker, and DAPI was established. The ImmuNet machine learning pipeline was trained for the detection of DC subsets. The performance of ImmuNet was compared with conventional cell phenotyping software. Ultimately, frequencies of DC subsets within several tumors were defined. In conclusion, this panel provides a method to study cDC1s, cDC2s, and pDCs in the spatial context of the TME, which supports unraveling their specific roles in antitumor immunity.
In this paper, we describe the development, validation, and quantitative analysis of a multiplex immunohistochemistry panel pipeline with which conventional type 1 dendritic cells (cDC1s), cDC2s, and plasmacytoid DCs can be detected in the spatial context of the tumor microenvironment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The efficacy of PD-1 blocking agents in advanced NSCLC has shown prolonged effectiveness, but only in a minority of patients. Multiple biomarkers have been explored to predict treatment benefit, yet ...their combined performance remains inadequately examined. In this study, we assessed the combined predictive performance of multiple biomarkers in NSCLC patients treated with nivolumab. Pretreatment samples from 135 patients receiving nivolumab were used to evaluate the predictive performance of CD8 tumor-infiltrating lymphocytes (TILs), intratumoral (IT) localization of CD8 TILs, PD-1 high expressing TILs (PD1.sup.T TILs), CD3 TILs, CD20 B-cells, tertiary lymphoid structures (TLS), PD-L1 tumor proportion score (TPS) and the Tumor Inflammation score (TIS). Patients were randomly assigned to a training (n = 55) and validation cohort (n = 80). The primary outcome measure was Disease Control at 6 months (DC 6m) and the secondary outcome measure was DC at 12 months (DC 12m). In the validation cohort, the two best performing composite biomarkers (i.e. CD8+IT-CD8 and CD3+IT-CD8) demonstrated similar or lower sensitivity (64% and 83%) and NPV (76% and 85%) compared to individual biomarkers PD-1.sup.T TILs and TIS (sensitivity: 72% and 83%, NPV: 86% and 84%) for DC 6m, respectively. Additionally, at 12 months, both selected composite biomarkers (CD8+IT-CD8 and CD8+TIS) demonstrated inferior predictive performance compared to PD-1.sup.T TILs and TIS alone. PD-1.sup.T TILs and TIS showed high sensitivity (86% and 100%) and NPV (95% and 100%) for DC 12m. PD-1.sup.T TILs could more accurately discriminate patients with no long-term benefit, as specificity was substantially higher compared to TIS (74% versus 39%). Composite biomarkers did not show improved predictive performance compared to PD-1.sup.T TILs and TIS alone for both the 6- and 12-month endpoints. PD-1.sup.T TILs and TIS identified patients with DC 12m with high sensitivity. Patients with no long-term benefit to PD-1 blockade were most accurately identified by PD-1.sup.T TILs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an ...excessive proinflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis revealed no specific inflammatory endotypes in COVID-19 patients. Functional assays revealed abrogated adaptive cytokine production (interferon-γ, interleukin-17, and interleukin-22) and prominent T-cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlights potential biomarkers of disease severity.
Increasing COVID-19 disease severity is characterized by higher circulating levels of inflammatory markers, differential expression of HGF (higher) and SCF (lower), a hyperinflammatory innate immune system, and a severely dysfunctional adaptive immune system.
Malignant pleural effusion (MPE) causes debilitating breathlessness and predicting survival is challenging. This study aimed to obtain contemporary data on survival by underlying tumour type in ...patients with MPE, identify prognostic indicators of overall survival and develop and validate a prognostic scoring system.
Three large international cohorts of patients with MPE were used to calculate survival by cell type (univariable Cox model). The prognostic value of 14 predefined variables was evaluated in the most complete data set (multivariable Cox model). A clinical prognostic scoring system was then developed and validated.
Based on the results of the international data and the multivariable survival analysis, the LENT prognostic score (pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group (ECOG) performance score (PS), neutrophil-to-lymphocyte ratio and tumour type) was developed and subsequently validated using an independent data set. Risk stratifying patients into low-risk, moderate-risk and high-risk groups gave median (IQR) survivals of 319 days (228-549; n=43), 130 days (47-467; n=129) and 44 days (22-77; n=31), respectively. Only 65% (20/31) of patients with a high-risk LENT score survived 1 month from diagnosis and just 3% (1/31) survived 6 months. Analysis of the area under the receiver operating curve revealed the LENT score to be superior at predicting survival compared with ECOG PS at 1 month (0.77 vs 0.66, p<0.01), 3 months (0.84 vs 0.75, p<0.01) and 6 months (0.85 vs 0.76, p<0.01).
The LENT scoring system is the first validated prognostic score in MPE, which predicts survival with significantly better accuracy than ECOG PS alone. This may aid clinical decision making in this diverse patient population.
Stage II–IIIA nonsmall cell lung cancer (NSCLC) patients receive adjuvant chemotherapy after surgery as standard‐of‐care treatment, even though only approximately 5.8% of patients will benefit. ...Identifying patients with minimal residual disease (MRD) after surgery using tissue‐informed testing of postoperative plasma circulating cell‐free tumour DNA (ctDNA) may allow adjuvant therapy to be withheld from patients without MRD. However, the detection of MRD in the postoperative setting is challenging, and more sensitive methods are urgently needed. We developed a method that combines variant calling and a novel ctDNA fragment length analysis using hybrid capture sequencing data. Among 36 stage II–IIIA NSCLC patients, this method distinguished patients with and without recurrence of disease in a 20 times repeated 10‐fold cross validation with 75% accuracy (P = 0.0029). In contrast, using only variant calling or only fragment length analysis, no signification distinction between patients was shown (P = 0.24 and P = 0.074 respectively). In addition, a variant‐level fragmentation score was developed that was able to classify variants detected in plasma cfDNA into tumour‐derived or white‐blood‐cell‐derived variants with 84% accuracy. The findings in this study may help drive the integration of various types of information from the same data, eventually leading to cheaper and more sensitive techniques to be used in this challenging clinical setting.
Blood and tissue from 36 stage II–III NSCLC patients and 15 risk‐ and age‐matched patients with nonmalignant disease were analysed with targeted hybrid capture sequencing to detect postsurgery minimal residual disease (MRD) in the blood, prior to adjuvant therapy. Our combined variant calling and fragmentomics MRD model was capable of stratifying patients with and without recurrence with 75% accuracy (P = 0.0029).
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Correlations between increasing concentrations of circulating tumor DNA (ctDNA) in plasma and disease progression have been shown. A nonlinear mixed effects model to describe the dynamics of ...epidermal growth factor receptor (EGFR) ctDNA data from patients with non‐small cell lung cancer (NSCLC) combined with a parametric survival model were developed to evaluate the ability of these modeling techniques to describe ctDNA data. Repeated ctDNA measurements on L858R, exon19del, and T790M mutants were available from 54 patients with EGFR mutated NSCLC treated with erlotinib or gefitinib. Different dynamic models were tested to describe the longitudinal ctDNA concentrations of the driver and resistance mutations. Subsequently, a parametric time‐to‐event model for progression‐free survival (PFS) was developed. Predicted L858R, exon19del, and T790M concentrations were used to evaluate their value as predictor for disease progression. The ctDNA dynamics were best described by a model consisting of a zero‐order increase and first‐order elimination (19.7/day, 95% confidence interval CI 14.9–23.6/day) of ctDNA concentrations. In addition, time‐dependent development of resistance (5.0 × 10−4, 95% CI 2.0 × 10−4–7.0 × 10−4/day) was included in the final model. Relative change in L858R and exon19del concentrations from baseline was identified as most significant predictor of disease progression (p = 0.001). The dynamic model for L858R, exon19del, and T790M concentrations in ctDNA and time‐to‐event model adequately described the observed concentrations and PFS data in our clinical cohort. In addition, it was shown that nonlinear mixed effects modeling is a valuable method for the analysis of longitudinal and heterogeneous biomarker datasets obtained from clinical practice.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in ...patients with metastatic non-small cell lung cancer.
To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer.
This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018.
Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy.
The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.
Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio HR, 0.76; 97.54% CI, 0.56-1.02; P = .04 nonsignificant). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months 95% CI, 11.4-32.8 vs 10.0 months 95% CI, 8.1-11.7; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively.
The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab.
ClinicalT rials.gov Identifier: NCT02453282.
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