scholarly journals Detection of Immune Checkpoint Receptors – A Current Challenge in Clinical Flow Cytometry

2021 ◽  
Vol 12 ◽  
Author(s):  
Benjamin Shibru ◽  
Katharina Fey ◽  
Stephan Fricke ◽  
André-René Blaudszun ◽  
Friederike Fürst ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune System ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Neurological Diseases ◽  
Modern Medicine ◽  
Functional Markers ◽  
Immunological Therapy ◽  
Target Molecules ◽  
Checkpoint Receptors

Immunological therapy principles are increasingly determining modern medicine. They are used to treat diseases of the immune system, for tumors, but also for infections, neurological diseases, and many others. Most of these therapies base on antibodies, but small molecules, soluble receptors or cells and modified cells are also used. The development of immune checkpoint inhibitors is amazingly fast. T-cell directed antibody therapies against PD-1 or CTLA-4 are already firmly established in the clinic. Further targets are constantly being added and it is becoming increasingly clear that their expression is not only relevant on T cells. Furthermore, we do not yet have any experience with the long-term systemic effects of the treatment. Flow cytometry can be used for diagnosis, monitoring, and detection of side effects. In this review, we focus on checkpoint molecules as target molecules and functional markers of cells of the innate and acquired immune system. However, for most of the interesting and potentially relevant parameters, there are still no test kits suitable for routine use. Here we give an overview of the detection of checkpoint molecules on immune cells in the peripheral blood and show examples of a possible design of antibody panels.

Immune checkpoint inhibitors: review of the existing evidence and challenges in breast cancer

Immunotherapy ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 587-603
Author(s):  
Mobina Jalalvand ◽  
Farzaneh Darbeheshti ◽  
Nima Rezaei
Keyword(s):  
Breast Cancer ◽  
Immune System ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Breast Cancer Patients ◽  
Body Of Knowledge ◽  
Us Fda ◽  
Checkpoint Receptors

Cancer initiation and progression are associated with immune system responses. Tumor cells use various tricks to scape of immune system, such as activating immune checkpoint pathways that induce immunosuppressive functions. Among the different immune checkpoint receptors, CTLA-4 and PD-1/PD-L1 are prominent therapeutic targets in different cancers. Although the US FDA has approved some immune checkpoint inhibitors for several cancers, concerning breast cancer still different clinical trials are looking for optimizing efficacy and decreasing immune-related adverse events. This review will discuss the existing body of knowledge with regard to cross-talk between immune system and tumor cells and then explore immune checkpoint-related signaling pathways in the context of breast tumors. Finally, we highlight the application of different immune checkpoint blockers in breast cancer patients.

scholarly journals Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 561
Author(s):  
Anca Bobircă ◽  
Florin Bobircă ◽  
Ioan Ancuta ◽  
Alesandra Florescu ◽  
Vlad Pădureanu ◽  
...  
Keyword(s):  
Immune System ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Multidisciplinary Approach ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Cancer Cell Growth ◽  
Inhibitory Mechanisms ◽  
Checkpoint Inhibitor Therapy

The advent of immunotherapy has changed the management and therapeutic methods for a variety of malignant tumors in the last decade. Unlike traditional cytotoxic chemotherapy, which works by interfering with cancer cell growth via various pathways and stages of the cell cycle, cancer immunotherapy uses the immune system to reduce malignant cells’ ability to escape the immune system and combat cell proliferation. The widespread use of immune checkpoint inhibitors (ICIs) over the past 10 years has presented valuable information on the profiles of toxic adverse effects. The attenuation of T-lymphocyte inhibitory mechanisms by ICIs results in immune system hyperactivation, which, as expected, is associated with various adverse events defined by inflammation. These adverse events, known as immune-related adverse events (ir-AEs), may affect any type of tissue throughout the human body, which includes the digestive tract, endocrine glands, liver and skin, with reports of cardiovascular, pulmonary and rheumatic ir-AEs as well. The adverse events that arise from ICI therapy are both novel and unique compared to those of the conventional treatment options. Thus, they require a multidisciplinary approach and continuous updates on the diagnostic approach and management.

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

IMMU-06. COMBINATORIAL IMMUNE CHECKPOINT INHIBITORS FOR TARGETED INTRATUMORAL DELIVERY IN GBM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi93-vi93
Author(s):  
Stephanie Sanders ◽  
Denise Herpai ◽  
Waldemar Debinski
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Live Cells ◽  
Normal Brain ◽  
Cytotoxic Therapies ◽  
Checkpoint Receptors

Abstract Glioblastoma (GBM) is an immunologically cold tumor. Using single cell sequencing of CD45+ cells we confirmed that T cells are present within GBM samples. These T cells are positive for exhaustion markers such as LAG3 and TIGIT, as well as CTLA4 and PD1 checkpoint receptors. Modulating T cell activity through use of immune checkpoint inhibitors (ICIs) has shown efficacy in the treatment of a variety of solid tumors, and the combination of anti-CTLA4 and anti-PD1 ICIs has shown increased efficacy over use of a single therapeutic. Additionally, targeting ICIs to the tumor cells may increase efficacy of this treatment. We therefore constructed a combinatorial ICI redirected to GBM via interleukin 13 receptor alpha 2 (IL13RA2), a receptor over-expressed on the majority of GBM cells but not normal brain. The first component of the construct, labeled with a histidine tag, targets CTLA4 while the second component, tagged with a StrepII tag, targets PD1. The tags added to the constructs will allow for purification of a combinatorial heterodimer simultaneously targeting PD1, CTLA4 and IL13RA2. We purified individual components via fast protein liquid chromatography (FPLC) using a proteinG column followed by a HisTrap or StrepTrap column. We obtained a recombinant, targeted multivalent ICI at > 95% purity. We found that these constructs are able to bind their target receptors via ELISA in which the Kd values ranged from picomolar to low nanomolar range. Additionally, our constructs bind their target on live cells by flow cytometry. We next designed a heterodimeric construct which can combinatorially target CTLA4 and PD1 while also directing the ICI therapy to GBM. These constructs in conjunction with other immune stimulants like cytotoxic therapies are intended to facilitate the interaction between T cells and GBM tumor cells directly in a tumor microenvironment.

scholarly journals Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy

Gut ◽  
2018 ◽  
Vol 67 (10) ◽  
pp. 1845-1854 ◽  
Author(s):  
Yue Zhao ◽  
Timothy Wai Ho Shuen ◽  
Tan Boon Toh ◽  
Xue Ying Chan ◽  
Min Liu ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Immune Checkpoint ◽  
Drug Testing ◽  
Checkpoint Inhibitors ◽  
Tumour Microenvironment ◽  
Human Immune System ◽  
Patient Derived Xenograft ◽  
Human Immune ◽  
Human Specific

ObjectiveAs the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.DesignPatient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg−/− (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.ResultsSimilar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.ConclusionsOur work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.

Gut Microbiota and Immune Checkpoint Inhibitors-Based Immunotherapy

2021 ◽  
Vol 21 ◽  
Author(s):  
Mingming Tian ◽  
Si Zhang ◽  
Yujen Tseng ◽  
Xizhong Shen ◽  
Ling Dong ◽  
...  
Keyword(s):  
Immune System ◽  
Gut Microbiota ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Recent Progress ◽  
Checkpoint Inhibitors ◽  
Antitumor Response ◽  
Number Of Patients ◽  
Cancer Types ◽  
Patients Experience

: Application of immune checkpoint inhibitors (ICIs) is a major breakthrough in the field of cancer therapy, which has displayed tremendous potential in various types of malignancies. However, their response rates range widely in different cancer types and a significant number of patients experience immune-related adverse effects (irAEs) induced by these drugs, limiting the proportion of patients who can truly benefit from ICIs. Gut microbiota has gained increasing attention due to its emerging role in regulating the immune system. In recent years, numerous studies have shown that gut microbiota can modulate antitumor response, as well as decrease the risk of colitis due to ICIs in patients receiving immunotherapy. The present review analyzed recent progress of relevant basic and clinical studies in this area and explored new perspectives to enhance the efficacy of ICIs and alleviate associated irAEs via manipulation of the gut microbiota.

scholarly journals Surface-Enhanced Raman Spectroscopy for Cancer Immunotherapy Applications: Opportunities, Challenges, and Current Progress in Nanomaterial Strategies

Nanomaterials ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 1145 ◽  
Author(s):  
Shuvashis Dey ◽  
Matt Trau ◽  
Kevin M. Koo
Keyword(s):  
Raman Spectroscopy ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Surface Enhanced Raman Spectroscopy ◽  
Surface Enhanced ◽  
Surface Enhanced Raman ◽  
Checkpoint Receptors

Cancer immunotherapy encompasses a variety of approaches which target or use a patient’s immune system components to eliminate cancer. Notably, the current use of immune checkpoint inhibitors to target immune checkpoint receptors such as CTLA-4 or PD-1 has led to remarkable treatment responses in a variety of cancers. To predict cancer patients’ immunotherapy responses effectively and efficiently, multiplexed immunoassays have been shown to be advantageous in sensing multiple immunomarkers of the tumor microenvironment simultaneously for patient stratification. Surface-enhanced Raman spectroscopy (SERS) is well-regarded for its capabilities in multiplexed bioassays and has been increasingly demonstrated in cancer immunotherapy applications in recent years. This review focuses on SERS-active nanomaterials in the modern literature which have shown promise for enabling cancer patient-tailored immunotherapies, including multiplexed in vitro and in vivo immunomarker sensing and imaging, as well as immunotherapy drug screening and delivery.

scholarly journals Cancer Immunotherapy by Blocking Immune Checkpoints on Innate Lymphocytes

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3504
Author(s):  
Silvia Pesce ◽  
Sara Trabanelli ◽  
Clara Di Vito ◽  
Marco Greppi ◽  
Valentina Obino ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Lymphoid Cells ◽  
Immune Checkpoints ◽  
Tissue Damages ◽  
Innate Lymphocytes

Immune checkpoints refer to a plethora of inhibitory pathways of the immune system that play a crucial role in maintaining self-tolerance and in tuning the duration and amplitude of physiological immune responses to minimize collateral tissue damages. The breakdown of this delicate balance leads to pathological conditions, including cancer. Indeed, tumor cells can develop multiple mechanisms to escape from immune system defense, including the activation of immune checkpoint pathways. The development of monoclonal antibodies, targeting inhibitory immune checkpoints, has provided an immense breakthrough in cancer therapy. Immune checkpoint inhibitors (ICI), initially developed to reverse functional exhaustion in T cells, recently emerged as important actors in natural killer (NK)-cell-based immunotherapy. Moreover, the discovery that also helper innate lymphoid cells (ILCs) express inhibitory immune checkpoints, suggests that these molecules might be targeted on ILCs, to modulate their functions in the tumor microenvironment. Recently, other strategies to achieve immune checkpoint blockade have been developed, including miRNA exploiting systems. Herein, we provide an overview of the current knowledge on inhibitory immune checkpoints on NK cells and ILCs and we discuss how to target these innate lymphocytes by ICI in both solid tumors and hematological malignancies.

scholarly journals Challenge of immune-mediated adverse reactions in the emergency department

2019 ◽  
Vol 36 (6) ◽  
pp. 369-377 ◽  
Author(s):  
Gregory A Daniels ◽  
Angela D Guerrera ◽  
Donna Katz ◽  
Jayne Viets-Upchurch
Keyword(s):  
Immune System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Adverse Reactions ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
High Dose ◽  
Clear Understanding ◽  
Immune Mediated ◽  
Multiple Drugs

Multiple drugs of a new class of cancer treatments called immune checkpoint inhibitors, which work by enabling the immune system to attack tumour cells, have been approved for a variety of indications in recent years. Immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 and programmed death-1, are part of the normal immune system and regulate immune activation. Treatment with inhibitors of these checkpoints can significantly improve response rates, progression-free survival and overall survival of patients with cancer; it can also result in adverse reactions that present similarly to other conditions. These immune-mediated adverse reactions (IMARs) are most commonly gastrointestinal, respiratory, endocrine or dermatologic. Although patients’ presentations may appear similar to other types of cancer therapy, the underlying causes, and consequently their management, may differ. Prompt recognition is critical because, with appropriate management, most IMARs resolve and patients can continue receiving immune checkpoint inhibitor treatment. Rarely, these IMARs may be life-threatening and escape detection from the usual evaluations in the emergency environment. Given the unusual spectrum and mechanism of IMARs arising from immune checkpoint inhibitors, emergency departmentED staff require a clear understanding of the evaluation of IMARs to enable them to appropriately assess and treat these patients. Treatment of IMARs, most often with high-dose steroids, differs from chemotherapy-related adverse events and when possible should be coordinated with the treating oncologist. This review summarises the ED presentation and management of IMARs arising from immune checkpoint inhibitors and includes recommendations for tools and resources for ED healthcare professionals.

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