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 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 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 Virotherapy as a Potential Therapeutic Approach for the Treatment of Aggressive Thyroid Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1532 ◽  
Author(s):  
Malfitano ◽  
Somma ◽  
Prevete ◽  
Portella
Keyword(s):  
Thyroid Carcinoma ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Differentiated Thyroid Carcinoma ◽  
Anaplastic Thyroid Carcinoma ◽  
Oncolytic Viruses ◽  
Cancer Models ◽  
Poorly Differentiated ◽  
Immunosuppressive Microenvironment

Virotherapy is a novel cancer treatment based on oncolytic viruses (OVs), which selectively infect and lyse cancer cells, without harming normal cells or tissues. Several viruses, either naturally occurring or developed through genetic engineering, are currently under investigation in clinical studies. Emerging reports suggesting the immune-stimulatory property of OVs against tumor cells further support the clinical use of OVs for the treatment of lesions lacking effective therapies. Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), have a poor prognosis and limited treatment options. Therefore, several groups investigated the therapeutic potential of OVs in PDTC/ATC models producing experimental data sustaining the potential clinical efficacy of OVs in these cancer models. Moreover, the presence of an immunosuppressive microenvironment further supports the potential use of OVs in ATC. In this review, we present the results of the studies evaluating the efficacy of OVs alone or in combination with other treatment options. In particular, their potential therapeutic combination with multiple kinases inhibitors (MKIs) or immune checkpoint inhibitors are discussed.

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 Combinatorial Approach to Improve Cancer Immunotherapy: Rational Drug Design Strategy to Simultaneously Hit Multiple Targets to Kill Tumor Cells and to Activate the Immune System

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Shweta Joshi ◽  
Donald L. Durden
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Rational Drug Design ◽  
Therapeutic Interventions ◽  
Epigenetic Therapy ◽  
T Cell Therapy

Cancer immunotherapy, including immune checkpoint blockade and adoptive CAR T-cell therapy, has clearly established itself as an important modality to treat melanoma and other malignancies. Despite the tremendous clinical success of immunotherapy over other cancer treatments, this approach has shown substantial benefit to only some of the patients while the rest of the patients have not responded due to immune evasion. In recent years, a combination of cancer immunotherapy together with existing anticancer treatments has gained significant attention and has been extensively investigated in preclinical or clinical studies. In this review, we discuss the therapeutic potential of novel regimens combining immune checkpoint inhibitors with therapeutic interventions that (1) increase tumor immunogenicity such as chemotherapy, radiotherapy, and epigenetic therapy; (2) reverse tumor immunosuppression such as TAMs, MDSCs, and Tregs targeted therapy; and (3) reduce tumor burden and increase the immune effector response with rationally designed dual or triple inhibitory chemotypes.

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 Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part II—The Challenge of Programmed Death Ligand-1 Testing and Its Role in Microsatellite Instability-High Colorectal Cancer

2017 ◽  
Vol 142 (1) ◽  
pp. 26-34 ◽  
Author(s):  
Esmeralda Celia Marginean ◽  
Barbara Melosky
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Microsatellite Instability ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Immune Checkpoints ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

Context.— The world of oncology has changed dramatically in the past few years with the introduction of checkpoint inhibitors and immunotherapy. The promising findings of a small, phase 2 clinical trial that led to the US Food and Drug Administration breakthrough designation and approval of the anti–programmed death receptor-1 (PD-1) drug pembrolizumab (Keytruda, Merck, Kenilworth, New Jersey) to treat metastatic/refractory microsatellite instability–high colorectal cancer (CRC) has significantly boosted interest in immunomodulatory therapies in microsatellite instability–high CRC. Objectives.— To review the immune response to cancer and the role of immune checkpoints, focusing on the technical and interpretation challenges of PD-1/programmed death ligand-1 (PD-L1) testing by pathologists and the clinical implications of the test and the therapeutic potential of treating CRC with checkpoint inhibitors. Data Sources.— A PubMed review was performed of articles pertaining to CRC, microsatellite instability and mismatch repair systems, molecular classification, immune response, PD-1/PD-L1, and immunotherapy. Conclusions.— Exciting success with anti–PD-1/PD-L1 and anticytotoxic T-lymphocyte–associated protein 4 (CTLA4) checkpoint inhibitors has already been reported in melanoma and in lung and renal carcinomas. Recently, microsatellite instability–high CRCs, expressing PD-L1 by immunohistochemistry, regardless of the level of that PD-L1 expression, appeared to respond to checkpoint blockades with anti–PD-1 or anti–PD-L1 agents, whereas microsatellite-stable tumors were much less responsive. With microsatellite instability routinely tested by most centers, studies that include larger cohorts are required to study the predictive role of PD-1/PD-L1 expression in microsatellite instability–high CRC, to assess which immunohistochemistry antibodies to use, to refine the scoring criteria, and to critically analyze the interpretation pitfalls.

scholarly journals Regulating the immunosuppressive tumor microenvironment to enhance breast cancer immunotherapy using pH-responsive hybrid membrane-coated nanoparticles

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chunai Gong ◽  
Xiaoyan Yu ◽  
Wei Zhang ◽  
Lu Han ◽  
Rong Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Adenosine Monophosphate ◽  
Great Promise ◽  
Ph Responsive ◽  
Programmed Death ◽  
Biomimetic Membrane

AbstractThe combination of an immuno-metabolic adjuvant and immune checkpoint inhibitors holds great promise for effective suppression of tumor growth and invasion. In this study, a pH-responsive co-delivery platform was developed for metformin (Met), a known immuno-metabolic modulator, and short interfering RNA (siRNA) targeting fibrinogen-like protein 1 mRNA (siFGL1), using a hybrid biomimetic membrane (from macrophages and cancer cells)-camouflaged poly (lactic-co-glycolic acid) nanoparticles. To improve the endo-lysosomal escape of siRNA for effective cytosolic siRNA delivery, a pH-triggered CO2 gas-generating nanoplatform was developed using the guanidine group of Met. It can react reversibly with CO2 to form Met-CO2 for the pH-dependent capture/release of CO2. The introduction of Met, a conventional anti-diabetic drug, promotes programmed death-ligand 1 (PD-L1) degradation by activating adenosine monophosphate-activated protein kinase, subsequently blocking the inhibitory signals of PD-L1. As a result, siFGL1 delivery by the camouflaged nanoparticles of the hybrid biomimetic membrane can effectively silence the FGL1 gene, promoting T-cell-mediated immune responses and enhancing antitumor immunity. We found that a combination of PD-L1/programmed death 1 signaling blockade and FGL1 gene silencing exhibited high synergistic therapeutic efficacy against breast cancer in vitro and in vivo. Additionally, Met alleviated tumor hypoxia by reducing oxygen consumption and inducing M1-type differentiation of tumor-related macrophages, which improved the tumor immunosuppressive microenvironment. Our results indicate the potential of hybrid biomimetic membrane-camouflaged nanoparticles and combined Met-FGL1 blockade in breast cancer immunotherapy.

scholarly journals Statins Decrease Programmed Death-Ligand 1 (PD-L1) by Inhibiting AKT and β-Catenin Signaling

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2488
Author(s):  
Woo-Jin Lim ◽  
Mingyu Lee ◽  
Yerin Oh ◽  
Xue-Quan Fang ◽  
Sujin Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
De Novo ◽  
Antibody Therapy ◽  
Programmed Death Ligand 1 ◽  
Cancer Models ◽  
Programmed Death ◽  
Previously Treated ◽  
Cell Death Protein ◽  
Mouse Cancer Models

Retrospective observational studies have reported that statins improve clinical outcomes in patients previously treated with programmed cell death protein 1 (PD-1)-targeting monoclonal antibodies for malignant pleural mesothelioma (MPM) and advanced non-small cell lung cancer (NSCLC). In multiple mouse cancer models, de novo synthesis of mevalonate and cholesterol inhibitors was found to synergize with anti-PD-1 antibody therapy. In the present study, we investigated whether statins affect programmed death-ligand 1 (PD-L1) expression in cancer cells. Four statins, namely simvastatin, atorvastatin, lovastatin, and fluvastatin, decreased PD-L1 expression in melanoma and lung cancer cells. In addition, we found that AKT and β-catenin signaling involved PD-L1 suppression by statins. Our cellular and molecular studies provide inspiring evidence for extending the clinical evaluation of statins for use in combination with immune checkpoint inhibitor-based cancer therapy.

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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