scholarly journals On the Horizon: Targeting Next-Generation Immune Checkpoints for Cancer Treatment

Chemotherapy ◽  
2019 ◽  
Vol 64 (2) ◽  
pp. 62-80 ◽  
Author(s):  
Grazia R. Tundo ◽  
Diego Sbardella ◽  
Pedro M. Lacal ◽  
Grazia Graziani ◽  
Stefano Marini
Keyword(s):  
Monoclonal Antibodies ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Immune Checkpoints ◽  
Next Generation ◽  
Therapeutic Success ◽  
Regulatory Pathways ◽  
Pharmacological Targets ◽  
Inhibitory Molecules

Background: Immune checkpoints are critical regulatory pathways of the immune system which finely tune the response to biological threats. Among them, the CD-28/CTLA-4 and PD-1/PD-L1 axes play a key role in tumour immune escape and are well-established targets of cancer immunotherapy. Summary: The clinical experience accumulated to date provides unequivocal evidence that anti-CTLA-4, PD-1, or PD-L1 monoclonal antibodies, used as monotherapy or in combination regimes, are effective in a variety of advanced/metastatic types of cancer, with improved clinical outcomes compared to conventional chemotherapy. However, the therapeutic success is currently restricted to a limited subset of patients and reliable predictive biomarkers are still lacking. Key Message: The identification and characterization of additional co-inhibitory pathways as novel pharmacological targets to improve the clinical response in refractory patients has led to the development of different immune checkpoint inhibitors, the activities of which are currently under investigation. In this review, we discuss recent literature data concerning the mechanisms of action of next-generation monoclonal antibodies targeting LAG-3, TIM-3, and TIGIT co-inhibitory molecules that are being explored in clinical trials, as single agents or in combination with other immune-stimulating agents.

scholarly journals Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

2020 ◽  
Author(s):  
Jie Mei ◽  
Yun Cai ◽  
Rui Xu ◽  
Xuejing Yang ◽  
Weijian Zhou ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Survival Data ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Methylation Status ◽  
Low Grade Glioma ◽  
Immune Checkpoints ◽  
Low Grade ◽  
Programmed Death

AbstractBackgroundImmune checkpoints play crucial roles in immune escape of cancer cells. However, the exact prognostic values of expression and methylation of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1) and PD-L2 in low-grade glioma (LGG) have not been defined yet.MethodsA total of 514 LGG samples from TCGA dataset containing both PD-1, PD-L1 and PD-L2 expression, DNA methylation, and survival data were enrolled into our study. The clinical significance of PD-1/PD-Ls expression and methylation in LGG were explored. Besides, the correlation between PD-1/PD-Ls expression and methylation with the infiltration levels of tumor-infiltrating immune cells (TIICs) was assessed. Moreover, GO enticement analysis of PD-1/PD-Ls co-expressed genes was performed as well. R 3.6.2 and GraphPad Prism 8 were applied as main tools for the statistical analysis and graphical exhibition.ResultsPD-1/PD-Ls had distinct co-expression patterns in LGG tissues. The expression and methylation status of PD-1/PD-Ls seemed to be various in different LGG subtypes. Besides, upregulated PD-1/PD-Ls expression and hypo-methylation of PD-1/PD-Ls were associated with worse survival in LGG patients. In addition, PD-1/PD-Ls expression was revealed to be positively associated with TIICs infiltration, while their methylation was negatively associated with TIICs infiltration. Moreover, the PD-1/PDLs correlated gene profiles screening and Gene Ontology (GO) enrichment analysis uncovered that PD-1/PDLs and their positively correlated gene mainly participated in immune response related biological processes.ConclusionsHigh expression and hypo-methylation of PD-1/PD-Ls significantly correlated with unfavorable survival in LGG patients, suggesting LGG patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.

scholarly journals Checkpoint Inhibitors and Their Application in Breast Cancer

Breast Care ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. 108-115 ◽  
Author(s):  
Davide Bedognetti ◽  
Cristina Maccalli ◽  
Salha B.J. Al Bader ◽  
Francesco M. Marincola ◽  
Barbara Seliger
Keyword(s):  
Breast Cancer ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Immune Surveillance ◽  
Significant Proportion ◽  
Immune Checkpoints ◽  
Immune Recognition ◽  
Breast Cancers ◽  
Inhibitory Molecules

Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently under clinical development. In this review, we summarize the evidence supporting the implementation of checkpoint inhibition in breast cancer by reviewing in detail data on PD-L1 expression and its regulation. In addition, opportunities to boost anti-tumor immunity in breast cancer with checkpoint inhibitor-based immunotherapies alone and in combination with other treatment options will be discussed.

scholarly journals A “Lymphocyte MicroRNA Signature” as Predictive Biomarker of Immunotherapy Response and Plasma PD-1/PD-L1 Expression Levels in Patients with Metastatic Renal Cell Carcinoma: Pointing towards Epigenetic Reprogramming

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3396
Author(s):  
Lorena Incorvaia ◽  
Daniele Fanale ◽  
Giuseppe Badalamenti ◽  
Chiara Brando ◽  
Marco Bono ◽  
...  
Keyword(s):  
Clinical Decision Making ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Clinical Decision ◽  
Mirna Expression Profile ◽  
Immune Checkpoints ◽  
Cancer Evolution ◽  
Specific Subset ◽  
Number Of Patients

Introduction of checkpoint inhibitors resulted in durable responses and improvements in overall survival in advanced RCC patients, but the treatment efficacy is widely variable, and a considerable number of patients are resistant to PD-1/PD-L1 inhibition. This variability of clinical response makes necessary the discovery of predictive biomarkers for patient selection. Previous findings showed that the epigenetic modifications, including an extensive microRNA-mediated regulation of tumor suppressor genes, are key features of RCC. Based on this biological background, we hypothesized that a miRNA expression profile directly identified in the peripheral lymphocytes of the patients before and after the nivolumab administration could represent a step toward a real-time monitoring of the dynamic changes during cancer evolution and treatment. Interestingly, we found a specific subset of miRNAs, called “lymphocyte miRNA signature”, specifically induced in long-responder patients (CR, PR, or SD to nivolumab >18 months). Focusing on the clinical translational potential of miRNAs in controlling the expression of immune checkpoints, we identified the association between the plasma levels of soluble PD-1/PD-L1 and expression of some lymphocyte miRNAs. These findings could help the development of novel dynamic predictive biomarkers urgently needed to predict the potential response to immunotherapy and to guide clinical decision-making in RCC patients.

scholarly journals Immunotherapy in hematologic malignancies

2019 ◽  
Vol 27 (S2) ◽  
Author(s):  
R.R. Kansara ◽  
C. Speziali
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Hematologic Malignancies ◽  
Immune Checkpoints ◽  
Hematologic Neoplasms

The management of hematologic malignancies has traditionally relied on chemotherapy regimens, many of which are still in use today. However, with advancements in the knowledge of tumour pathophysiology, therapies are continually evolving. Monoclonal antibodies against specific targets on tumour cells are now widely used to treat hematologic malignancies, either in combination with chemotherapy or as single agents. Rituximab, a monoclonal antibody against the CD20 antigen, is a good example of successful monoclonal antibody therapy that has improved outcomes for patients with B cell non-Hodgkin lymphomas. Monoclonal antibodies are now being used against the immune checkpoints that function to inhibit T cell activation and subsequent tumour eradication by those cytotoxic T cells. Such therapies enhance T cell–mediated tumour eradication and are widely successful in treating patients with solid tumours such as malignant melanoma. Now, they are slowly finding their place in the management of hematologic neoplasms. Even though, currently, immune checkpoint inhibitors are used for relapsed or refractory hematologic neoplasms, trials are ongoing to evaluate their role in frontline treatment. Our review focuses on the current use of immunotherapies in various hematologic malignancies.

scholarly journals Immune metabolism in PD-1 blockade-based cancer immunotherapy

2020 ◽  
Vol 33 (1) ◽  
pp. 17-26
Author(s):  
Alok Kumar ◽  
Kenji Chamoto
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Cancer Cell ◽  
Metabolic Regulation ◽  
Immune Cell ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Abstract Energy metabolism plays an important role in proliferating cells. Recent reports indicate that metabolic regulation or metabolic products can control immune cell differentiation, fate and reactions. Cancer immunotherapy based on blockade of programmed cell death protein 1 (PD-1) has been used worldwide, but a significant fraction of patients remain unresponsive. Therefore, clarifying the mechanisms and overcoming the unresponsiveness are urgent issues. Because cancer immunity consists of interactions between the cancer and host immune cells, there has recently been a focus on the metabolic interactions and/or competition between the tumor and the immune system to address these issues. Cancer cells render their microenvironment immunosuppressive, driving T-cell dysfunction or exhaustion, which is advantageous for cancer cell survival. However, accumulating mechanistic evidence of T-cell and cancer cell metabolism has gradually revealed that controlling the metabolic pathways of either type of cell can overcome T-cell dysfunction and reprogram the metabolic balance in the tumor microenvironment. Here, we summarize the role of immune metabolism in T-cell-based immune surveillance and cancer immune escape. This new concept has boosted the development of combination therapy and predictive biomarkers in cancer immunotherapy with immune checkpoint inhibitors.

scholarly journals Characterization of the Clinical Significance of PD-1/PD-Ls Expression and Methylation in Patients With Low-Grade Glioma

2021 ◽  
Vol 20 ◽  
pp. 153303382110119
Author(s):  
Jie Mei ◽  
Yun Cai ◽  
Rui Xu ◽  
Xuejing Yang ◽  
Weijian Zhou ◽  
...  
Keyword(s):  
Survival Data ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Low Grade Glioma ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Low Grade ◽  
Programmed Death ◽  
Genome Atlas

Background: Immune checkpoints play crucial roles in the immune escape of cancer cells. However, the exact prognostic values of expression and methylation of programmed-death 1 (PD-1), programmed-death-ligand 1 (PD-L1) and PD-L2 in low-grade glioma (LGG) have not been well-defined yet. Methods: A total 514 LGG samples from the Cancer Genome Atlas (TCGA) dataset containing gene expression, DNA methylation, and survival data were enrolled in our study. Besides, a total of 137 primary LGG samples from the Chinese Glioma Genome Atlas (CGGA) database were also extracted for the survival analysis of the prognostic values of PD-1/PD-Ls expression. Results: PD-1/PD-Ls had distinct co-expression patterns in LGG tissues. The expression and methylation level of PD-1/PD-Ls seemed to be various in different LGG subtypes. Besides, overexpression and hypo-methylation of PD-1/PD-Ls were associated with worse prognosis. In addition, PD-1/PD-Ls expression was positively associated with TIICs infiltration, while their methylation was negatively associated with TIICs infiltration. Moreover, PD-1/PD-Ls and their positively correlated gene mainly participated in immune response related biological processes. Conclusion: To conclude, overexpression and hypo-methylation of PD-1/PD-Ls predicted unfavorable prognosis in LGG patients, suggesting those patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.

scholarly journals Predictive biomarkers of inhibitors immune checkpoints therapy in malignant tumors

2021 ◽  
Vol 8 (2) ◽  
pp. 73-83
Author(s):  
M. V. Kiselevsky ◽  
I. V. Samoylenko ◽  
O. V. Zharkova ◽  
N. V. Ziganshina ◽  
A. A. Petkevich ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Predictive Biomarkers ◽  
Peripheral Blood Lymphocytes ◽  
Immune Checkpoints ◽  
Russian Science ◽  
Programmed Death ◽  
Number Of Patients ◽  
Russian Science Citation Index

Immune checkpoint inhibitors (ICT) therapy is a successful immunotherapy (IT) strategy that is quite effective in a number of patients with non-small cell lung cancer, melanoma, bladder cancer, breast cancer and others. Nevertheless, there is a need in predictive markers for ICT therapy for personalized IT as far as there is a large group of patients, the proportion of which varies depending on the tumor, who do not have a clinical response to such therapy. The review summarizes the theoretical aspects and results of clinical trials dedicated to various clinical efficiency predictor using modern databases. As a result of the analysis it is established that the main candidates for the role of such markers are tumor infiltrating lymphocytes and their subpopulations, peripheral blood lymphocytes (PBL) and their subpopulations. PD1 (programmed death receptor 1) and PDL1 (programmed death receptor ligand 1) expression in tumor tissue can also be important for predicting IT efficiency. The most promising predictive biomarker meaning the most clinically relevant is a combination of the PBL subpopulations study and PD1 and PDL1 expression on the tumor cells.PubMed, Scopus, Web of Science, eLibrary, Russian Science Citation Index databases were searched for the available appropriate literature reports. The authors included 82 in the given review.

scholarly journals BTLA-HVEM Couple in Health and Diseases: Insights for Immunotherapy in Lung Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Clemence Demerlé ◽  
Laurent Gorvel ◽  
Daniel Olive
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Tumor Immune Escape ◽  
Promising Target ◽  
Tnf Receptor Family ◽  
Receptor Family

Lung cancer is the leading cause of cancer deaths worldwide. Immunotherapies (IT) have been rapidly approved for lung cancer treatment after the spectacular results in melanoma. Responses to the currently used checkpoint inhibitors are strikingly good especially in metastatic diseases. However, durable responses are observed in only 25% of cases. Consequently, there is an urgent need for new immunotherapy targets. Among the multiple checkpoints involved in the tumor immune escape, the BTLA-HVEM couple appears to be a promising target. BTLA (B- and T- Lymphocyte Attenuator) is a co-inhibitory receptor mainly expressed by B and T cells, repressing the activation signal transduction. BTLA shares similarities with other immune checkpoints such as PD-1 and CTLA-4 which are the targets of the currently used immunotherapies. Furthermore, BTLA expression points out terminally exhausted and dysfunctional lymphocytes, and correlates with lung cancer progression. The ligand of BTLA is HVEM (Herpes Virus Entry Mediator) which belongs to the TNF receptor family. Often described as a molecular switch, HVEM is constitutively expressed by many cells, including cells from tumor and healthy tissues. In addition, HVEM seems to be involved in tumor immuno-evasion, especially in lung tumors lacking PD-L1 expression. Here, we propose to review the role of BTLA-HVEM in immuno-escape in order to highlight its potential for designing new immunotherapies.

scholarly journals Immune-checkpoint engagement as predictive biomarkers in clear cell renal cell carcinoma and melanoma

2020 ◽  
Author(s):  
Lissete Sánchez-Magraner ◽  
James Miles ◽  
Claire Baker ◽  
Christopher J Applebee ◽  
Dae-Jin Lee ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Predictive Biomarkers ◽  
Immune Checkpoints ◽  
Ligand Interaction ◽  
Receptor Ligand ◽  
Programmed Death ◽  
Cell Cell

ABSTRACTMany cancers are termed immuno-evasive due to expression of immuno-modulatory ligands. Programmed death ligand-1 (PD-L1) and cluster of differentiation 80/86 (CD80/86) interact with their receptors, programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4), on tumour infiltrating leukocytes, thus eliciting immunosuppression. Immunotherapies aimed at blocking these interactions are revolutionising cancer treatments, albeit in an inadequately described patient subset.Our prognostic assay, utilising amplified two-site time-resolved Förster resonance energy transfer (iFRET), quantifies PD-1/ PD-L1 and CTLA-4/ CD80 cell-cell interactions in single cell assays and tumour biopsies. iFRET efficiencies demonstrate, in cell-cell engagement models, that receptor-ligand interactions are significantly lower with anti-PD-1 or anti-CTLA-4 blocking antibodies. In patient samples, iFRET detects immune-cell/tumour-cell interaction variance in different cancers. These results revealed inter-cancer, inter-patient and intra-tumoural heterogeneity of engaged immune-checkpoints, contradicting their ligand expression patterns. Exploiting spatio-temporal interactions of immune-checkpoint proteins defined biomarker functionality for determining whether checkpoint inhibitors are appropriate treatments.Statement of SignificanceQuantitative photophysics exploitation in determining immune-checkpoint engagement, as predictive biomarkers in cancers led to revealing inter-cancer, inter-patient and intra-tumoural heterogeneity of the engaged immune-checkpoints. This receptor-ligand interaction did not reflect simple expression patterns of these immuno-modulatory proteins. Our findings may affect immunotherapies aimed at blocking these intercellular interactions in patients.

scholarly journals Patients Selection for Immunotherapy in Solid Tumors: Overcome the Naïve Vision of a Single Biomarker

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Diego Signorelli ◽  
Patrizia Giannatempo ◽  
Giulia Grazia ◽  
Marco Maria Aiello ◽  
Federica Bertolini ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Clinical Evaluation ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Nonsmall Cell Lung Cancer ◽  
Immune Checkpoints ◽  
Clinical Value ◽  
Programmed Death ◽  
Number Of Patients

Immunotherapy, and in particular immune-checkpoints blockade therapy (ICB), represents a new pillar in cancer therapy. Antibodies targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Programmed Death 1 (PD-1)/Programmed Death Ligand-1 (PD-L1) demonstrated a relevant clinical value in a large number of solid tumors, leading to an improvement of progression free survival and overall survival in comparison to standard chemotherapy. However, across different solid malignancies, the immune-checkpoints inhibitors efficacy is limited to a relative small number of patients and, for this reason, the identification of positive or negative predictive biomarkers represents an urgent need. Despite the expression of PD-L1 was largely investigated in various malignancies, (i.e., melanoma, head and neck malignancies, urothelial and renal carcinoma, metastatic colorectal cancer, and pancreatic cancer) as a biomarker for ICB treatment-patients selection, it showed an important, but still imperfect, role as positive predictor of response only in nonsmall cell lung cancer (NSCLC). Importantly, other tumor and/or microenvironments related characteristics are currently under clinical evaluation, in combination or in substitution of PD–L1 expression. In particular, tumor-infiltrating immune cells, gene expression analysis, mismatch- repair deficiency, and tumor mutational landscape may play a central role in predicting clinical benefits of CTLA-4 and/or PD-1/PD-L1 checkpoint inhibitors. In this review, we will focus on the clinical evaluation of emerging biomarkers and how these may improve the naïve vision of a single- feature patients-based selection.

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