The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC

Background: Immune checkpoint inhibitors improve outcomes compared with chemotherapy in lung cancer. Tumor PD-L1 receptor expression is being studied as a predictive biomarker. The objective of this study was to assess the cost-effectiveness and economic impact of second-line treatment with nivolumab, pembrolizumab, and atezolizumab with and without the use of PD-L1 testing for patient selection. Design: We developed a decision-analytic model to determine the cost-effectiveness of PD-L1 assessment and second-line immunotherapy versus docetaxel. The model used outcomes data from randomized clinical trials (RCTs) and drug acquisition costs from the United States. Thereafter, we used epidemiologic data to estimate the economic impact of the treatment. Results: We included four RCTs (2 with nivolumab, 1 with pembrolizumab, and 1 with atezolizumab). The incremental quality-adjusted life year (QALY) for nivolumab was 0.417 among squamous tumors and 0.287 among non-squamous tumors and the incremental cost-effectiveness ratio (ICER) were $155 605 and$187 685, respectively. The QALY gain in the base case for atezolizumab was 0.354 and the ICER was $215 802. Compared with treating all patients, the selection of patients by PD-L1 expression improved incremental QALY by up to 183$98 421. Patient selection also reduced the budget impact of immunotherapy. Conclusion: The use of PD-L1 expression as a biomarker increases cost-effectiveness of immunotherapy but also diminishes the number of potential life-years saved.info:eu-repo/semantics/publishedVersio

The exercise-triggered release of extracellular vesicles into the circulation

Physical exercise induces acute physiological changes leading to massively enhanced cross-talk between cells, organs, and tissues. These acute alterations cause systemic adaptations which promote physical and mental health on a long-term. Though, the molecular basis underlying these bodily adaptations remains elusive. Extracellular vesicles (EVs) are cell-derived membranous entities which transport bioactive material and function as mediators of cell-cell-communication between several organs and tissues. EVs in the circulation increase upon diverse exercise interventions and are speculated to be involved in the physiological adaptation processes induced by regular physical exercise. However, knowledge on the dynamics, the origin, and the composition of EVs present in blood during and after exercise (ExerVs) is poor. In addition, the difficulties in EV-isolation from blood plasma represents a hurdle for the characterization of ExerVs. Here, a detailed analysis of different ExerV subclasses to define their release kinetics and their origin was performed in an incremental cycling exercise setting involving 21 healthy male athletes. EV isolation via size exclusion chromatography (SEC), immuno-affinity capture as well as combination of SEC with density gradient centrifugation lead to enrichment of EVs from human plasma samples. Semi-quantitative analyses of ExerV dynamics in SEC-EVs and immuno-affinity captured EVs revealed elevations in a load-response related fashion. Phenotyping of ExerVs using two multiplexed analysis approaches directly in blood plasma or isolated SEC-EVs, CD9+EVs, CD63+EVs, and CD81+EVs revealed a panel of cellular marker proteins present on ExerVs. The results indicate that ExerVs originate from leukocytes, including lymphocytes (CD4+EVs, CD8+EVs), monocytes (CD14+EVs) and antigen presenting cells (MHCI+EVs, MHCII+EVs), as well as endothelial cells (CD105+EVs, CD146+EVs), and platelets (CD41b+EVs, CD62P+EVs). Impaired downstream analysis of proteomic content, nanoparticle tracking analysis, and imaging flow cytometry analysis of differentially isolated ExerVs demonstrated the need for further improvement of EV purity to gain deeper insights on actual concentrations and the composition of ExerVs. Conclusively, various cell types of the circulatory system contribute to the exercise-triggered release of extracellular vesicles into the blood stream. This heterogeneous pool of ExerVs may be involved in signaling processes associated with coagulation, endothelial function and inflammation.Körperliche Aktivität löst eine akute Stressreaktion aus, welche starke Veränderungen von physiologischen Parameter mit sich bringt. Diese akuten Veränderungen verursachen systemische Anpassungen, die langfristig die körperliche und geistige Gesundheit fördern. Die zugrundeliegenden Mechanismen sind jedoch noch nicht völlig geklärt. Extrazelluläre Vesikel (EVs) sind von Zellen abgegebene membranumschlossene Einheiten, die bioaktives Material transportieren und als Vermittler der Zell-zu-Zell-Kommunikation zwischen verschiedenen Organen und Geweben fungieren. Die Menge an EVs in der Zirkulation nimmt in Folge verschiedener körperlicher Betätigungen zu und es wird spekuliert, dass EVs an physiologischen Anpassungsprozessen beteiligt sind, welche durch regelmäßige körperliche Bewegung ausgelöst werden. Das Wissen über die Dynamik, den Ursprung und die Zusammensetzung von EVs, die während und nach dem Sport im Blut zu finden sind (bezeichnet als „ExerVs“), ist jedoch begrenzt. Zudem stellt die erschwerte Isolation von EVs aus Blutplasma eine Hürde für die Charakterisierung von ExerVs dar. Hier wurde eine detaillierte Analyse verschiedener ExerV-Subklassen mit dem Ziel einer genauen Beschreibung ihrer Freisetzungskinetik und ihrer zellulären Herkunft durchgeführt. Dafür wurden 21 gesunde männliche Athleten einem stufenweisen Ausbelastungstest auf dem Fahrradergometer unterzogen. Die EV-Isolierung mittels Größenausschlusschromatographie (englisch „size exclusion chromatography“ = SEC), Immunaffinitäts-Isolation sowie die Kombination von SEC mit Dichtegradientenzentrifugation führten zur Anreicherung von EVs aus Blutplasma. Semi-quantitative Analysen der ExerV-Dynamik in SEC-EVs und Immunaffinität-isolierten EVs ergaben Anstiege über den Verlauf der Belastung. Die Phänotypisierung von ExerVs mittels zweier Multiplex-Analysemethoden direkt im Blutplasma oder mit isolierten SEC-EVs, CD9+EVs, CD63+EVs und CD81+EVs ergab eine Reihe an zellulären Markerproteinen, die auf ExerVs zu finden sind. Die Ergebnisse deuten darauf hin, dass ExerVs von Leukozyten, einschließlich Lymphozyten (CD4+EVs, CD8+EVs), Monozyten (CD14+EVs) und antigenpräsentierenden Zellen (MHCI+EVs, MHCII+EVs), sowie Endothelzellen (CD105+EVs, CD146+EVs) und Thrombozyten (CD41b+EVs, CD62P+EVs), freigesetzt werden. Die massive Beeinträchtigung der Analyse des Proteoms von verschieden isolierten ExerVs, sowie der Nanopartikel-Tracking-Analyse und der bildgebenden Durchflusszytometrie verdeutlicht die Notwendigkeit einer weiteren Verbesserung der EV-Reinheit, um tiefere Einblicke in die tatsächlichen Konzentrationen und die Zusammensetzung von ExerVs zu erhalten. Schlussendlich kann festgehalten werden, dass verschiedene Zelltypen des Kreislaufsystems während physischer Belastung dazu beitragen, dass extrazelluläre Vesikel ins Blut abgegeben werden. Diese heterogenen ExerV Spezies könnten an Signalprozessen beteiligt sein, die in Zusammenhang mit Koagulation, Endothelfunktion und Inflammation stehen

Immune checkpoint inhibitors for advanced non-small cell lung cancer: emerging sequencing for new treatment targets

Lung cancer is the leading cause of cancer-related deaths in the world. Immune checkpoint inhibitors (ICI) stimulate cytotoxic lymphocyte activity against tumour cells. These agents are available for the treatment of nonsmall cell lung cancer (NSCLC) after failure of platinumbased therapy. One recent study has demonstrated that ICI monotherapy was superior to platinum-based chemotherapy for first-line treatment. Nevertheless, this benefit was only for a minority of the population (30%) whose tumour programmed death receptor ligand-1 (PD-L1) expression was above 50%. Therefore, several strategies are under investigation. One option for patients with PD-L1 expression lower than 50% may be the combination of ICI with platinum-based chemotherapy or with ICIs against different targets. However, all of these combinations are at an early stage of investigation and may be very expensive or toxic, producing several harmful adverse events.info:eu-repo/semantics/publishedVersio

Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151912/1/apt15413-sup-0001-FigS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151912/2/apt15413.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151912/3/apt15413_am.pd

Alterations of immune response of non-small lung cancer with azacytidine

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade

Experiences of cancer immunotherapy with immune checkpoint inhibitors (ExCIm)—insights of people affected by cancer and healthcare professionals: a qualitative study protocol

ntroduction There is a global interest in cancer immunotherapy. Clinical trials have found that one group, immune checkpoint inhibitors (ICIs), has demonstrated clinical benefits across various cancers. However, research focused on the experiences of people affected by cancer who have undergone this treatment using qualitative methodology is currently limited. Moreover, little is known about the experiences and education needs of the healthcare staff supporting the people receiving these immunotherapies. This study therefore seeks to explore the experiences of using ICIs by both the people affected by cancer and the healthcare professionals who support those people, and use the findings to make recommendations for ICI supportive care guidance development, cancer immunotherapy education materials for healthcare professionals, cancer policy and further research. Methods and analysis Patient participants (n=up to 30) will be recruited within the UK. The sample will incorporate a range of perspectives, sociodemographic factors, diagnoses and ICI treatments, yet share some common experiences. Healthcare professionals (n=up to 15) involved in supporting people receiving immunotherapy will also be recruited from across the UK. Data will be generated through in-depth, semistructured interviews. Reflexive thematic analysis will be used to obtain thorough understanding of individual’s perspectives on, and experiences of, immunotherapy. Study dates are as follows: December 2019–March 2022. Ethics and dissemination The research will be performed in accordance with the UK Policy for Health and Social Care Research and Cardiff University’s Research Integrity and Governance Code of Practice (2018). The study received ethical approval from the West Midlands and Black Country Research Ethics Committee in October 2019. Health Research Authority and Health and Care Research Wales approvals were confirmed in December 2019. All participants will provide informed consent. Findings will be published in peer-reviewed journals, non-academic platforms, the Macmillan Cancer Support website, disseminated at relevant national and international conferences and presented via a webinar. The study is listed on the National Institute for Health Research (NIHR) Clinical Research Network Central Portfolio

ヒト食道扁平上皮癌におけるherpesvirus entry mediator関与の重要性

BACKGROUND:Herpesvirus entry mediator (HVEM) is known to regulate immune response and to be expressed in several human malignancies. However, to the authors's knowledge, the precise role of HVEM in human cancer biology remains unknown. The objective of the current study was to clarify the clinical significance of HVEM in human esophageal squamous cell carcinoma as well as its in vivo functions.METHODS:HVEM expression was evaluated in 103 patients with esophageal squamous cell carcinoma to explore its clinical relevance and prognostic value. The functions of HVEM in tumors were analyzed in vitro and in vivo using the small interfering RNA (siRNA) silencing technique. RESULTS:HVEM expression was found to be significantly correlated with depth of tumor invasion and lymph node metastasis. Furthermore, it was found to be inversely correlated with tumor-infiltrating CD4(+) , CD8(+) , and CD45RO(+) lymphocytes. It is important to note that HVEM status was identified as an independent prognostic marker. HVEM gene silencing significantly inhibited cancer cell proliferation in vitro and cancer growth in vivo. This antitumor effect was associated with reduced cell proliferation activity. The effect was also correlated with the induction of CD8(+) cells and upregulation of local immune response.CONCLUSIONS:HVEM plays a critical role in both tumor progression and the evasion of host antitumor immune responses, possibly through direct and indirect mechanisms. Therefore, HVEM may be a promising therapeutic target for human esophageal cancer.博士（医学）・乙第1337号・平成26年5月28日Copyright © 1999-2015 John Wiley & Sons, Inc. All Rights Reserved.© 2013 American Cancer Societ

Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50.

Purpose We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS).Methods Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point.Results Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti-PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3-40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48-0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure.Conclusion Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%

TLR9 Mediated Tumor-Stroma Interactions in Human Papilloma Virus (HPV)-Positive Head and Neck Squamous Cell Carcinoma Up-Regulate PD-L1 and PD-L2

Background: The co-inhibitory receptor PD-1 is expressed in many tumors including head and neck squamous cell carcinoma (HNSCC) and is an important immunotherapy target. However, the role of PD-1 ligands, PD-L1, and particularly PD-L2, in the tumor-stromal cell interactions that cause a tumor-permissive environment in HNSCC is not completely understood and is the focus of our study. Methods: Expression of PD-L1 and PD-L2 was analyzed by immunohistochemistry in situ in HNSCC tumor tissue. Co-cultures were established between stromal cells (fibroblasts and macrophages) and human papilloma virus (HPV)-positive and HPV-negative HNSCC cell lines (HNSCCs) and PD-1 ligands expression was analyzed using flow cytometry. Results: PD-L1 and PD-L2 were expressed both in tumor cells and stroma in HNSCC tissue in situ. In vitro, basal expression of PD-L1 and PD-L2 was low in HNSCCs and high on fibroblasts and macrophages. Interestingly, HPV-positive but not HPV-negative HNSCCs increased the expression of both PD-1 ligands on fibroblasts upon co-culture. This effect was not observed with macrophages. Conversely, both fibroblasts and macrophages increased PD-1 ligands on HPV-positive HNSCCs, whilst this was not observed in HPV-negative HNSCCs. Crucially, we demonstrate that up-regulation of PD-L1 and PD-L2 on fibroblasts by HPV-positive HNSCCs is mediated via TLR9. Conclusions: This work demonstrates in an in vitro model that HPV-positive HNSCCs regulate PD-L1/2 expression on fibroblasts via TLR9. This may open novel avenues to modulate immune checkpoint regulator PD-1 and its ligands by targeting TLR9