438 Synergy between SEA-CD40 and chemotherapeutics drives curative antitumor activity in preclinical models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A464-A464
Author(s):  
Weiping Zeng ◽  
Haley Neff-LaFord ◽  
Sahar Ansari ◽  
Celine Jacquemont ◽  
Michael Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Cell Activation ◽  
Tumor Antigens ◽  
Immune Cell ◽  
Chemotherapeutic Agents ◽  
Clinical Development ◽  
Immune Cell Activation

BackgroundCD40 is a co-stimulatory receptor of the TNF receptor superfamily expressed on antigen presenting cells (APCs). Antibodies targeting CD40 may have antitumor therapeutic benefit by driving innate immune cell activation that supports generation of antigen-specific T cell responses. Multiple CD40-directed antibodies are in clinical development in both solid and hematologic indications and differ according to immunoglobulin isotype, affinity to CD40, and differential FcγR-binding. SEA-CD40 is an agonistic nonfucosylated, humanized IgG1 monoclonal antibody directed against CD40. SEA-CD40 is distinct from other CD40 targeted agents in clinical development as it binds with increased affinity to FcγRIIIa resulting in enhanced effector function and CD40 agonism. This unique composition of SEA-CD40 could amplify immune stimulation and antitumor activity relative to other CD40-directed therapeutics.MethodsEffective immunity requires the presence of diverse antigens to drive generation of distinct antigen-specific memory T cells. SEA-CD40 in many ways works like a vaccine as it can increase active acquired immunity against endogenous tumor antigens. A potential limiting factor for maximal SEA-CD40 antitumor activity across multiple tumor types may be the limited level and diversity of tumor-associated antigens within the tumor microenvironment (TME). Chemotherapeutic agents drive tumor cell death resulting in the release and increase of tumor antigens locally within the TME. Combining chemotherapeutic agents with SEA-CD40 could facilitate robust antigen release and amplified presentation of those antigens to CD8+ T cells. Antitumor activity and immune cell changes of SEA-CD40 in combination with chemotherapeutic agents was evaluated in vitro and in vivo using human CD40 transgenic mice.ResultsIn preclinical mouse models, SEA-CD40 combined with chemotherapeutic agents to drive robust anti-tumor activity. The nature of the chemotherapeutic agent influenced immune cell activation within the tumor microenvironment (TME) and extent of combinability with SEA-CD40. Preclinical assessment indicates that chemotherapeutics which induce immunogenic cell death (ICD) combine with SEA-CD40 to increase curative activity compared to non-ICD-inducing chemotherapeutics. The preferred partnership of SEA-CD40 with ICD-inducing agents, such as a monomethyl auristatin E (MMAE) antibody-drug conjugate, increased curative antitumor activity in mouse models. The combination of SEA-CD40 and chemotherapeutic agents with a T cell targeted anti-PD1 antibody could deepen and extend these anti-tumor responses.ConclusionsThese data support continued clinical evaluation of SEA-CD40 in combination with chemotherapeutic agents and potentially in the future MMAE based ADCs. A phase 1 clinical trial is actively enrolling (NCT02376699) and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab.Ethics ApprovalStudies with human samples were performed according to institutional ethics standards. Animals studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-029.

scholarly journals The Role of T Cells and Macrophages in Asthma Pathogenesis: A New Perspective on Mutual Crosstalk

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Xueyi Zhu ◽  
Jie Cui ◽  
La Yi ◽  
Jingjing Qin ◽  
Wuniqiemu Tulake ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Microenvironment ◽  
Innate And Adaptive Immunity ◽  
Immune Cell Activation ◽  
Inflammatory Signals ◽  
Macrophage Dysfunction ◽  
New Perspective

Asthma is associated with innate and adaptive immunity mediated by immune cells. T cell or macrophage dysfunction plays a particularly significant role in asthma pathogenesis. Furthermore, crosstalk between them continuously transmits proinflammatory or anti-inflammatory signals, causing the immune cell activation or repression in the immune response. Consequently, the imbalanced immune microenvironment is the major cause of the exacerbation of asthma. Here, we discuss the role of T cells, macrophages, and their interactions in asthma pathogenesis.

scholarly journals Immune Regulatory Processes of the Tumor Microenvironment under Malignant Conditions

2021 ◽  
Vol 22 (24) ◽  
pp. 13311
Author(s):  
Katrin Pansy ◽  
Barbara Uhl ◽  
Jelena Krstic ◽  
Marta Szmyra ◽  
Karoline Fechter ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Responses ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Escape ◽  
Large Fraction ◽  
Immune Cell Activation ◽  
Regulatory Processes ◽  
Membrane Bound ◽  
Tumor Entities

The tumor microenvironment (TME) is a critical regulator of tumor growth, progression, and metastasis. Since immune cells represent a large fraction of the TME, they play a key role in mediating pro- and anti-tumor immune responses. Immune escape, which suppresses anti-tumor immunity, enables tumor cells to maintain their proliferation and growth. Numerous mechanisms, which have been intensively studied in recent years, are involved in this process, and based on these findings, novel immunotherapies have been successfully developed. Here, we review the composition of the TME and the mechanisms by which immune evasive processes are regulated. In detail, we describe membrane-bound and soluble factors, their regulation, and their impact on immune cell activation in the TME. Furthermore, we give an overview of the tumor/antigen presentation and how it is influenced under malignant conditions. Finally, we summarize novel TME-targeting agents, which are already in clinical trials for different tumor entities.

scholarly journals Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Liting Xue ◽  
Xingyuan Gao ◽  
Haoyu Zhang ◽  
Jianxing Tang ◽  
Qian Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Development ◽  
Cell Mediated Immunity ◽  
Tumor Models ◽  
Anti Vegf

Abstract Background Signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage. Methods In this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. Results BD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells. Conclusions These data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

Hypertension

2021 ◽  
Vol 128 (7) ◽  
pp. 908-933
Author(s):  
Meena S. Madhur ◽  
Fernando Elijovich ◽  
Matthew R. Alexander ◽  
Ashley Pitzer ◽  
Jeanne Ishimwe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
Cardiovascular Risk ◽  
Cell Activation ◽  
Viral Infections ◽  
Immune Cell ◽  
Vascular Dysfunction ◽  
Dietary Salt ◽  
Activated T Cells ◽  
Immune Cell Activation

Elevated cardiovascular risk including stroke, heart failure, and heart attack is present even after normalization of blood pressure in patients with hypertension. Underlying immune cell activation is a likely culprit. Although immune cells are important for protection against invading pathogens, their chronic overactivation may lead to tissue damage and high blood pressure. Triggers that may initiate immune activation include viral infections, autoimmunity, and lifestyle factors such as excess dietary salt. These conditions activate the immune system either directly or through their impact on the gut microbiome, which ultimately produces chronic inflammation and hypertension. T cells are central to the immune responses contributing to hypertension. They are activated in part by binding specific antigens that are presented in major histocompatibility complex molecules on professional antigen-presenting cells, and they generate repertoires of rearranged T-cell receptors. Activated T cells infiltrate tissues and produce cytokines including interleukin 17A, which promote renal and vascular dysfunction and end-organ damage leading to hypertension. In this comprehensive review, we highlight environmental, genetic, and microbial associated mechanisms contributing to both innate and adaptive immune cell activation leading to hypertension. Targeting the underlying chronic immune cell activation in hypertension has the potential to mitigate the excess cardiovascular risk associated with this common and deadly disease.

scholarly journals cDC1 and interferons promote spontaneous CD4+ and CD8+ T cell protective responses to breast cancer

2020 ◽  
Author(s):  
Raphaël Mattiuz ◽  
Carine Brousse ◽  
Marc Ambrosini ◽  
Jean-Charles Cancel ◽  
Gilles Bessou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Antigens ◽  
Breast Cancer Patients ◽  
Ifn Γ ◽  
Cancer Immunosurveillance

AbstractHere we show that efficient breast cancer immunosurveillance relies on cDC1, conventional CD4+ T cells, CD8+ cytotoxic T lymphocytes (CTL) and later NK/NK T cells. For this process, cDC1 were required constitutively, but especially during the T cell priming phase. In the tumor microenvironment, cDC1 interacted physically and jointly with both CD4+ T cells and tumorspecific CD8+ T cells. We found that interferon (IFN) responses were necessary for the rejection of breast cancer, including cDC1-intrinsic signaling by IFN-γ and STAT1. Surprisingly, cell-intrinsic IFN-I signaling in cDC1 was not required. cDC1 and IFNs shaped the tumor immune landscape, notably by promoting CD4+ and CD8+ T cell infiltration, terminal differentiation and effector functions. XCR1, CXCL9, IL-12 and IL-15 were individually dispensable for breast cancer immunosurveillance. Consistent with our experimental results in mice, high expression in the tumor microenvironment of genes specific to cDC1, CTL, helper T cells or interferon responses are associated with a better prognosis in human breast cancer patients. Our results show that immune control of breast cancer depends on cDC1 and IFNs as previously reported for immunogenic melanoma or fibrosarcoma tumor models, but that the underlying mechanism differ. Revisiting cDC1 functions in the context of spontaneous immunity to cancer should help defining new ways to mobilize cDC1 functions to improve already existing immunotherapies for the benefits of patients.SynopsisType 1 conventional dendritic cells cross-present tumor antigens to CD8+ T cells. Understanding the regulation of their antitumor functions is important. Cell-intrinsic STAT1/IFN-γ signaling licenses them for efficient CD4+ and CD8+ T cell activation during breast cancer immunosurveillance.

scholarly journals Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6582-6588 ◽  
Author(s):  
Philippe Krebs ◽  
Karine Crozat ◽  
Daniel Popkin ◽  
Michael B. Oldstone ◽  
Bruce Beutler
Keyword(s):  
T Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Elevated Serum ◽  
Cytokine Signaling ◽  
Cell Contact ◽  
Inflammatory Disorder ◽  
Immune Cell Activation

AbstractHemophagocytic lymphohistiocytosis (HLH) is a rare inflammatory disorder with a poor prognosis for affected individuals. To find a means of suppressing the clinical phenotype, we investigated the cellular and molecular mechanisms leading to HLH in Unc13djinx/jinx mice, in which cytolytic function of NK and CD8+ T cells is impaired. Unc13djinx/jinx mutants infected with lymphochoriomeningitis virus (LCMV) present typical clinical features of HLH, including splenomegaly, elevated serum IFNγ, and anemia. Proteins mediating cell-cell contact, cytokine signaling or Toll-like receptor (TLR) signaling were analyzed. We show that neither the integrin CD18, which is involved in adhesion between antigen-presenting cells and effector T cells, nor tumor necrosis factor (TNF) made nonredundant contributions to the disease phenotype. Disruption of IFNγ signaling reduced immune cell activation in Unc13djinx/jinx mice, but also resulted in uncontrolled viral proliferation and exaggerated release of inflammatory cytokines. Abrogating the function of myeloid differentiation primary response gene 88 (MyD88) in Unc13djinx/jinx mice suppressed immune cell activation and controlled cytokine production in an IL-1 receptor 1 (IL-1R1)–independent way. Our findings implicate MyD88 as the key initiator of myeloid and lymphoid proliferation in HLH, and suggest that blockade of this signaling molecule may reduce immunopathology in patients.

scholarly journals 685 A highly selective and potent HPK1 inhibitor enhances immune cell activation and induces robust tumor growth inhibition in a murine syngeneic tumor model

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A724-A724
Author(s):  
David Ciccone ◽  
Vad Lazari ◽  
Ian Linney ◽  
Michael Briggs ◽  
Samantha Carreiro ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Tumor Model ◽  
Tumor Growth Inhibition ◽  
Immune Cell Activation ◽  
Syngeneic Tumor ◽  
Human T Cells

BackgroundHPK1, a member of the MAP4K family of protein serine/threonine kinases, is involved in regulating signal transduction cascades in cells of hematopoietic origin. Recent data from HPK1 knockout animals and kinase-inactive knock-in animals underscores the role of HPK1 in negatively regulating immune cell activation. This negative-feedback role of HPK1 combined with its restricted expression in cells of hematopoietic origin, make it a compelling drug target for enhancing anti-tumor immunity.MethodsA structure-based drug design approach was used to identify potent and selective inhibitors of HPK1. Biochemical assays, as well as primary human and mouse immune cell-based activation assays, were utilized for multiple iterations of structure-activity relationship (SAR) studies. In vivo efficacy, target engagement and pharmacodynamic data were generated using murine syngeneic tumor models.ResultsA highly potent, HPK1 inhibitor was identified, that showed high selectivity against T cell-specific kinases and kinases in the MAP4K family. In vitro, HPK1 small molecule inhibition resulted in enhanced IL-2 production in primary mouse and human T cells, enhanced IL-6 and IgG production in primary human B cells, and enhanced mouse dendritic cell activation and antigen presentation capacity. Furthermore, HPK1 inhibition alleviated the immuno-suppressive effects of PGE2 on naïve human T cells and restored the proliferative capacity of exhausted human T cells. In vivo, HPK1 inhibitionHPK1 inhibition abrogated T cell receptor-stimulated phospho-SLP-76, enhanced cytokine production, and mediated robust tumor growth inhibition in a murine syngeneic tumor model.ConclusionsPharmacological blockade of HPK1 kinase activity represents a novel and potentially valuable immunomodulatory approach for anti-tumor immunity.

scholarly journals Antiangiogenic Antibody BD0801 Combined With Immune Checkpoint Inhibitors Achieves Synergistic Antitumor Activity and Affects the Tumor Microenvironment

2021 ◽  
Author(s):  
Liting Xue ◽  
Xingyuan Gao ◽  
Haoyu Zhang ◽  
Qian Wang ◽  
Feng Li ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Development ◽  
Cell Mediated Immunity ◽  
Antiangiogenic Agents ◽  
Anti Vegf

Abstract Background: signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on the combination of anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage.Methods: this study revealed that BD0801 presents more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). We used the PK profile of BD0801 to guide the subsequent in vivo efficacy studies. Results: BD0801 exhibits dose-dependent tumor growth inhibitory activities in both xenograft and murine syngeneic tumor models. Combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies shows synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Mechanistic studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. The MOA of the antitumor synergy might involve enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells, reduced double-positive CD8+PD-1+ T cells, and improved vasculature normalization. Conclusions: these data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

Oxidized Haemoglobin–Driven Endothelial Dysfunction and Immune Cell Activation: Novel Therapeutic Targets for Atherosclerosis

2013 ◽  
Vol 20 (37) ◽  
pp. 4806-4814 ◽  
Author(s):  
Brigitta Buttari ◽  
Elisabetta Profumo ◽  
Rita Businaro ◽  
Luciano Saso ◽  
Raffaele Capoano ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Cell Activation ◽  
Immune Cell ◽  
Therapeutic Targets ◽  
Immune Cell Activation ◽  
Novel Therapeutic

scholarly journals Neuronal guidance proteins in cardiovascular inflammation

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Marius Keller ◽  
Valbona Mirakaj ◽  
Michael Koeppen ◽  
Peter Rosenberger
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Vascular Endothelial ◽  
Therapeutic Approaches ◽  
Immune Cell Activation ◽  
Cytokines And Chemokines ◽  
The Future ◽  
Cardiovascular Pathologies ◽  
Neuronal Guidance

AbstractCardiovascular pathologies are often induced by inflammation. The associated changes in the inflammatory response influence vascular endothelial biology; they complicate the extent of ischaemia and reperfusion injury, direct the migration of immune competent cells and activate platelets. The initiation and progression of inflammation is regulated by the classical paradigm through the system of cytokines and chemokines. Therapeutic approaches have previously used this knowledge to control the extent of cardiovascular changes with varying degrees of success. Neuronal guidance proteins (NGPs) have emerged in recent years and have been shown to be significantly involved in the control of tissue inflammation and the mechanisms of immune cell activation. Therefore, proteins of this class might be used in the future as targets to control the extent of inflammation in the cardiovascular system. In this review, we describe the role of NGPs during cardiovascular inflammation and highlight potential therapeutic options that could be explored in the future.

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