scholarly journals Improving the Diagnostic Accuracy of the PD-L1 Test with Image Analysis and Multiplex Hybridization

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1114 ◽  
Author(s):  
Matthew P. Humphries ◽  
Victoria Bingham ◽  
Fatima Abdullahi Sidi ◽  
Stephanie G. Craig ◽  
Stephen McQuaid ◽  
...  
Keyword(s):  
Image Analysis ◽  
Sensitivity And Specificity ◽  
Digital Image Analysis ◽  
Checkpoint Inhibitors ◽  
Diagnostic Testing ◽  
Programmed Death ◽  
Sensitivity Specificity ◽  
Nsclc Patients ◽  
Assessment Sensitivity ◽  
Cell Death Protein

Targeting of the programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis with checkpoint inhibitors has changed clinical practice in non-small cell lung cancer (NSCLC). However, clinical assessment remains complex and ambiguous. We aim to assess whether digital image analysis (DIA) and multiplex immunofluorescence can improve the accuracy of PD-L1 diagnostic testing. A clinical cohort of routine NSCLC patients reflex tested for PD-L1 (SP263) immunohistochemistry (IHC), was assessed using DIA. Samples of varying assessment difficulty were assessed by multiplex immunofluorescence. Sensitivity, specificity, and concordance was evaluated between manual diagnostic evaluation and DIA for chromogenic and multiplex IHC. PD-L1 expression by DIA showed significant concordance (R² = 0.8248) to manual assessment. Sensitivity and specificity was 86.8% and 91.4%, respectively. Evaluation of DIA scores revealed 96.8% concordance to manual assessment. Multiplexing enabled PD-L1+/CD68+ macrophages to be readily identified within PD-L1+/cytokeratin+ or PD-L1-/cytokeratin+ tumor nests. Assessment of multiplex vs. chromogenic IHC had a sensitivity and specificity of 97.8% and 91.8%, respectively. Deployment of DIA for PD-L1 diagnostic assessment is an accurate process of case triage. Multiplex immunofluorescence provided higher confidence in PD-L1 assessment and could be offered for challenging cases by centers with appropriate expertise and specialist equipment.

scholarly journals PD-L1 Targeting Immune-Microbubble Complex Enhances Therapeutic Index in Murine Colon Cancer Models

2020 ◽  
Vol 14 (1) ◽  
pp. 6
Author(s):  
Daehyun Kim ◽  
Seung Soo Lee ◽  
Hyungwon Moon ◽  
So Yeon Park ◽  
Hak Jong Lee
Keyword(s):  
Cancer Immunotherapy ◽  
Focused Ultrasound ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Therapeutic Index ◽  
Treatment Regimens ◽  
Cancer Models ◽  
Programmed Death ◽  
Murine Colon ◽  
Cell Death Protein

Cancer immunotherapy has revolutionized the way different neoplasms are treated. Among the different variations of cancer immunotherapy, the checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis have been validated and are currently used in the clinics. Nevertheless, these therapeutic antibodies are associated with significant side effects and are known to induce immune-related toxicities. To address these issues, we have developed an immune-microbubble complex (IMC) which not only reduces the toxicities associated with the antibodies but also enhances the therapeutic efficacy when combined with focused ultrasound. The concept of IMCs could be applied to any type of antibody-based treatment regimens to maximize their therapeutic potential.

scholarly journals Circulating Tumor Cell PD-L1 Expression as Biomarker for Therapeutic Efficacy of Immune Checkpoint Inhibition in NSCLC

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 809 ◽  
Author(s):  
Kloten ◽  
Lampignano ◽  
Krahn ◽  
Schlange
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Tissue Samples ◽  
Programmed Death ◽  
Nsclc Patients

Over the last decade, the immune checkpoint blockade targeting the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has improved progression-free and overall survival of advanced non-small cell lung cancer (NSCLC) patients. PD-L1 tumor expression, along with tumor mutational burden, is currently being explored as a predictive biomarker for responses to immune checkpoint inhibitors (ICIs). However, lung cancer patients may have insufficient tumor tissue samples and the high bleeding risk often prevents additional biopsies and, as a consequence, immunohistological evaluation of PD-L1 expression. In addition, PD-L1 shows a dynamic expression profile and can be influenced by intratumoral heterogeneity as well as the immune cell infiltrate in the tumor and its microenvironment, influencing the response rate to PD-1/PD-L1 axis ICIs. Therefore, to identify subgroups of patients with advanced NSCLC that will most likely benefit from ICI therapies, molecular characterization of PD-L1 expression in circulating tumor cells (CTCs) might be supportive. In this review, we highlight the use of CTCs as a complementary diagnostic tool for PD-L1 expression analysis in advanced NSCLC patients. In addition, we examine technical issues of PD-L1 measurement in tissue as well as in CTCs.

scholarly journals Blockade of PD-1, PD-L1, and TIM-3 Altered Distinct Immune- and Cancer-Related Signaling Pathways in the Transcriptome of Human Breast Cancer Explants

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 703
Author(s):  
Reem Saleh ◽  
Salman M. Toor ◽  
Dana Al-Ali ◽  
Varun Sasidharan Nair ◽  
Eyad Elkord
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Checkpoint Inhibitors ◽  
Rna Seq ◽  
Human Breast ◽  
Compensatory Mechanisms ◽  
Transcriptomic Data ◽  
Functional Studies ◽  
Programmed Death ◽  
Cell Death Protein

Immune checkpoint inhibitors (ICIs) are yet to have a major advantage over conventional therapies, as only a fraction of patients benefit from the currently approved ICIs and their response rates remain low. We investigated the effects of different ICIs—anti-programmed cell death protein 1 (PD-1), anti-programmed death ligand-1 (PD-L1), and anti-T cell immunoglobulin and mucin-domain containing-3 (TIM-3)—on human primary breast cancer explant cultures using RNA-Seq. Transcriptomic data revealed that PD-1, PD-L1, and TIM-3 blockade follow unique mechanisms by upregulating or downregulating distinct pathways, but they collectively enhance immune responses and suppress cancer-related pathways to exert anti-tumorigenic effects. We also found that these ICIs upregulated the expression of other IC genes, suggesting that blocking one IC can upregulate alternative ICs, potentially giving rise to compensatory mechanisms by which tumor cells evade anti-tumor immunity. Overall, the transcriptomic data revealed some unique mechanisms of the action of monoclonal antibodies (mAbs) targeting PD-1, PD-L1, and TIM-3 in human breast cancer explants. However, further investigations and functional studies are warranted to validate these findings.

scholarly journals Comparative Analysis of Predictive Biomarkers for PD-1/PD-L1 Inhibitors in Cancers: Developments and Challenges

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 109
Author(s):  
Fang Yang ◽  
Jacqueline F. Wang ◽  
Yucai Wang ◽  
Baorui Liu ◽  
Julian R. Molina
Keyword(s):  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Small Cell Lung ◽  
Genomic Signatures ◽  
Programmed Death ◽  
Life Threatening ◽  
Clinical Responses ◽  
Novel Biomarkers ◽  
Cell Death Protein

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have dramatically changed the landscape of cancer therapy. Both remarkable and durable responses have been observed in patients with melanoma, non-small-cell lung cancer (NSCLC), and other malignancies. However, the PD-1/PD-L1 blockade has demonstrated meaningful clinical responses and benefits in only a subset of patients. In addition, several severe and life-threatening adverse events were observed in these patients. Therefore, the identification of predictive biomarkers is urgently needed to select patients who are more likely to benefit from ICI therapy. PD-L1 expression level is the most commonly used biomarker in clinical practice for PD-1/PD-L1 inhibitors. However, negative PD-L1 expression cannot reliably exclude a response to a PD-1/PD-L1 blockade. Other factors, such as tumor microenvironment and other tumor genomic signatures, appear to impact the response to ICIs. In this review, we examine emerging data for novel biomarkers that may have a predictive value for optimizing the benefit from anti-PD-1/PD-L1 immunotherapy.

scholarly journals Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

2021 ◽  
Vol 11 ◽  
Author(s):  
Kenneth K. W. To ◽  
Winnie Fong ◽  
William C. S. Cho
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Poor Response ◽  
The Poor ◽  
Programmed Death ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Mutated ◽  
New Strategies

Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.

Validation of multiplex immunofluorescence and digital image analysis for programmed death-ligand 1 expression and immune cell assessment in non-small cell lung cancer: comparison with conventional immunohistochemistry

2021 ◽  
pp. jclinpath-2021-207448
Author(s):  
Jianghua Wu ◽  
Luning Mao ◽  
Wei Sun ◽  
Xin Yang ◽  
Haiyue Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Image Analysis ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Digital Image ◽  
Digital Image Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

AimsThis study aimed to validate the application of combined multiplex immunofluorescence (mIF) and digital image analysis (DIA) in formalin-fixed and paraffin-embedded tissues for the quantitative assessment of programmed death-ligand 1(PD-L1) and immune cells (ICs) in non-small cell lung cancer (NSCLC).MethodsFifty resected samples of NSCLC were sequentially stained with a DNA-tagged mIF (panel including PD-L1, CKpan, CD8, CD68 and 4′,6-diamidino-2-phenylindole (DAPI)) and conventional immunohistochemistry (cIHC). The assessment of cell density and consistency of tumour proportion score (TPS) via DIA were compared with those by pathologists.ResultsA strong correlation in the cell population of immune markers was obtained between mIF and cIHC (for PD-L1: R=0.9304, CKpan: R=0.8231, CD8: R=0.9314 and CD68: R=0.8366) within 95% limits of agreement. The continuous TPS calculated using mIF was highly consistent with the IHC staining results which were evaluated by pathologists (R=0.9362). However, in the comparison of TPS using interval variables, a poor agreement was obtained at a cut-off of 1% (κ=0.197), whereas excellent agreement was achieved at cut-offs of 50% (κ=0.908) and 5% (κ=0.823). DIA on mIF showed that PD-L1 commonly colocalised with CD68+ macrophages and CD8+ cytotoxic cells were closer to PD-L1-/CK+ tumour cells (TCs) than to PD-L1+/CK+ TCs in spatial distribution.ConclusionsA combination of mIF and DIA is useful for the quantification of PD-L1 expression and IC populations in NSCLC. Further validation of TPS at a cut-off of 1% and assay harmonisation is essential for translating this method in a diagnostic setting.

scholarly journals B7 Family Members in Lymphoma: Promising Novel Targets for Tumor Immunotherapy?

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Zhang ◽  
Yu Qiu ◽  
Xiaoli Xie ◽  
Yao Fu ◽  
Lijuan Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Vital Role ◽  
Immune Checkpoints ◽  
Programmed Death ◽  
B7 Family ◽  
Cell Death Protein

T cells play a vital role in the immune responses against tumors. Costimulatory or coinhibitory molecules regulate T cell activation. Immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have shown remarkable benefits in patients with various tumor, but few patients have displayed significant immune responses against tumors after PD-1/PD-L1 immunotherapy and many have been completely unresponsive. Thus, researchers must explore novel immune checkpoints that trigger durable antitumor responses and improve clinical outcomes. In this regard, other B7 family checkpoint molecules have been identified, namely PD-L2, B7-H2, B7-H3, B7-H4 and B7-H6. The aim of the present article was to address the expression, clinical significance and roles of B7 family molecules in lymphoma, as well as in T and NK cell-mediated tumor immunity. B7 family checkpoints may offer novel and immunotherapeutic strategies for patients with lymphoma.

scholarly journals Programmed death-ligand 1 expression by digital image analysis advances thyroid cancer diagnosis among encapsulated follicular lesions

Oncotarget ◽  
2018 ◽  
Vol 9 (28) ◽  
pp. 19767-19782 ◽  
Author(s):  
Anne M.-Y. Hsieh ◽  
Olena Polyakova ◽  
Guodong Fu ◽  
Ronald S. Chazen ◽  
Christina MacMillan ◽  
...  
Keyword(s):  
Image Analysis ◽  
Thyroid Cancer ◽  
Cancer Diagnosis ◽  
Digital Image ◽  
Digital Image Analysis ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Follicular Lesions

scholarly journals T follicular helper cells: linking cancer immunotherapy and immune-related adverse events

2021 ◽  
Vol 9 (6) ◽  
pp. e002588
Author(s):  
Dirk Baumjohann ◽  
Peter Brossart
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Underlying Mechanism ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Programmed Death ◽  
Cancer Types ◽  
Cell Death Protein

Cancer immunotherapy utilizing immune checkpoint inhibitors (ICIs) has revolutionized the treatment of numerous cancer types. As the underlying mechanism of these treatments lies in the interference with inhibitory signals that usually impair potent antitumor immunity, for example, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death protein 1 (PD-1):programmed death-ligand 1/2 (PD-L1/2) pathway, it is not surprising that this could also promote exaggerated adaptive immune responses to unrelated antigen specificities. One of the side effects of ICI-based cancer immunotherapy that is increasingly observed in the clinic is immune-related adverse events (irAEs), including various types of autoimmunity. However, the precise etiology is incompletely understood. T follicular helper (Tfh) cells provide essential help to B cells for potent antibody responses and their tumor tissue presence is often correlated with a better outcome in several solid tumor entities. Importantly, these CD4+ T cells express very high amounts of PD-1 and other co-stimulatory and inhibitory receptors. Here, we address the hypothesis that targeting CTLA-4 or PD-1 and its ligand PD-L1 critically impacts the function of Tfh cells in patients that receive these ICIs, thereby providing a link between ICI treatment and the development of secondary autoimmunity.

scholarly journals Immunotherapeutic Strategies for Gastric Carcinoma: A Review of Preclinical and Clinical Recent Development

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Mohamed Abozeid ◽  
Antonio Rosato ◽  
Roberta Sommaggio
Keyword(s):  
Gastric Carcinoma ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Adoptive T Cell Therapy ◽  
Poor Survival ◽  
T Cell Therapy ◽  
Surgical Interventions ◽  
Programmed Death ◽  
Preclinical And Clinical Studies ◽  
Cell Death Protein

Gastric carcinoma (GC) is the 2nd most common cause of cancer-related death. Despite advances in conventional treatment and surgical interventions, a high percentage of GC patients still have poor survival. Recently, immunotherapy has become a promising approach to treat GC. Here, we present preclinical and clinical studies encouraging the use of vaccination, adoptive T-cell therapy (ACT), and immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The ongoing immunotherapy clinical trials have shown promising results in safety and tolerability even in late-stage GC patients. Moreover, we highlight that the combination of ACT with chemotherapy could be the best choice to treat GC.

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