Many advances in the treatment of cancer have been driven by the development of targeted therapies that inhibit oncogenic signaling pathways and tumor-associated angiogenesis, as well as by the ...recent development of therapies that activate a patient's immune system to unleash antitumor immunity. Some targeted therapies can have effects on host immune responses, in addition to their effects on tumor biology. These immune-modulating effects, such as increasing tumor antigenicity or promoting intratumoral T cell infiltration, provide a rationale for combining these targeted therapies with immunotherapies. Here, we discuss the immune-modulating effects of targeted therapies against the MAPK and VEGF signaling pathways, and how they may synergize with immunomodulatory antibodies that target PD1/PDL1 and CTLA4. We critically examine the rationale in support of these combinations in light of the current understanding of the underlying mechanisms of action of these therapies. We also discuss the available preclinical and clinical data for these combination approaches and their implications regarding mechanisms of action. Insights from these studies provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of cancer.
IgE not only provides protective immunity against helminth parasites but can also mediate the type I hypersensitivity reactions that contribute to the pathogenesis of allergic diseases such as ...asthma, allergic rhinitis and atopic dermatitis. Despite the importance of IgE in immune biology and allergic pathogenesis, the cells and the pathways that produce and regulate IgE are poorly understood. In this Review, we summarize recent advances in our understanding of the production and the regulation of IgE in vivo, as revealed by studies in mice, and we discuss how these findings compare to what is known about human IgE biology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Therapeutics that target the T cell inhibitory checkpoint proteins CTLA-4 and PD(L)1 are efficacious across a broad range of cancers, resulting in reductions in tumor burden and increased long-term ...survival in subsets of patients. The significant and wide-ranging effects of these immunotherapies have prompted the clinical investigation of additional therapies that modulate anti-tumor immunity through effects on T cells, myeloid cells, and other cell types within the tumor microenvironment. The clinical activity of these newer investigational therapies has been mixed, with some therapeutics showing promise but others not exhibiting appreciable efficacy. In this review, we summarize the results of select recent clinical studies of cancer immunotherapies beyond anti-CTLA-4 and anti-PD(L)1 and discuss how these results are providing new insights into the regulation of human anti-tumor immunity.
Wu, Ouyang, and Egen review recent clinical studies of cancer immunotherapies beyond anti-CTLA-4 and anti-PD(L)1 and discuss therapeutic avenues that are showing promise and ones that do not seem to be working. In this context, they outline emerging insights into anti-tumor immunity with relevance both to the clinic and to our basic understanding of the interactions between tumors and the immune system.
Background Eosinophilic airway inflammation is heterogeneous in asthmatic patients. We recently described a distinct subtype of asthma defined by the expression of genes inducible by TH 2 cytokines ...in bronchial epithelium. This gene signature, which includes periostin, is present in approximately half of asthmatic patients and correlates with eosinophilic airway inflammation. However, identification of this subtype depends on invasive airway sampling, and hence noninvasive biomarkers of this phenotype are desirable. Objective We sought to identify systemic biomarkers of eosinophilic airway inflammation in asthmatic patients. Methods We measured fraction of exhaled nitric oxide (F eno ), peripheral blood eosinophil, periostin, YKL-40, and IgE levels and compared these biomarkers with airway eosinophilia in asthmatic patients. Results We collected sputum, performed bronchoscopy, and matched peripheral blood samples from 67 asthmatic patients who remained symptomatic despite maximal inhaled corticosteroid treatment (mean FEV1 , 60% of predicted value; mean Asthma Control Questionnaire ACQ score, 2.7). Serum periostin levels are significantly increased in asthmatic patients with evidence of eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. A logistic regression model, including sex, age, body mass index, IgE levels, blood eosinophil numbers, F eno levels, and serum periostin levels, in 59 patients with severe asthma showed that, of these indices, the serum periostin level was the single best predictor of airway eosinophilia ( P = .007). Conclusion Periostin is a systemic biomarker of airway eosinophilia in asthmatic patients and has potential utility in patient selection for emerging asthma therapeutics targeting TH 2 inflammation.
Highlights • IgE+ B cells in mice are predisposed to differentiate into short-lived plasma cells. • IgE+ B cells in mice do not persist in germinal centers. • Antibodies that inhibit IL-4 and/or ...IL-13 reduce serum IgE levels in allergic patients. • An antibody targeting membrane IgE inhibits new IgE production and reduces serum IgE levels in allergic patients. • A proportion of serum IgE is produced by short-lived plasma cells in allergic patients.
Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial ...tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Elevated IgE levels and increased IgE sensitization to allergens are central features of allergic asthma. IgE binds to the high-affinity Fcϵ receptor I (FcϵRI) on mast cells, basophils, and dendritic ...cells and mediates the activation of these cells upon antigen-induced cross-linking of IgE-bound FcϵRI. FcϵRI activation proceeds through a network of signaling molecules and adaptor proteins and is negatively regulated by a number of cell surface and intracellular proteins. Therapeutic neutralization of serum IgE in moderate-to-severe allergic asthmatics reduces the frequency of asthma exacerbations through a reduction in cell surface FcϵRI expression that results in decreased FcϵRI activation, leading to improved asthma control. Our increasing understanding of IgE receptor signaling may lead to the development of novel therapeutics for the treatment of asthma.
The cytokine interleukin 13 (IL-13) is a major effector molecule for T-helper type 2 inflammation and is pathogenic in allergic diseases such as asthma. The effects of IL-13 are mediated via a ...pathway that is initiated by binding to a heterodimeric receptor consisting of IL-13Rα1 and IL-4Rα. Antibodies raised against IL-13 can block its inflammatory effects by interfering with binding to either of the two receptor polypeptides. Lebrikizumab is a monoclonal anti-IL-13 antibody that has shown clinical benefit in a phase II study for the treatment of moderate-to-severe uncontrolled asthma. Here we report the molecular structure of IL-13 in complex with the Fab from lebrikizumab by X-ray crystallography at 1.9Å resolution. We show that lebrikizumab inhibits IL-13 signaling by binding to IL-13 with very high affinity and blocking IL-13 binding to IL-4Rα. In addition, we use site-directed mutations to identify the most important antibody contributors to binding. Our studies define key features of lebrikizumab binding and its mechanism of action that may contribute to its clinical effects.
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► The cytokine IL-13 is a major immune effector associated with asthma. ► Anti-IL-13 lebrikizumab has a dissociation constant less than 10pM. ► Lebrikizumab prevents binding of IL-4Rα, a receptor required for signaling.
Background Thymic stromal lymphopoietin (TSLP) is a cytokine implicated in the pathophysiology of asthma through 2 distinct pathways: a TSLP–OX40 ligand (OX40L)–T cell axis and a TSLP–mast cell axis. ...Whether these pathways are active in human asthma is unknown. Objective We sought to investigate whether mucosal TSLP protein expression relates to asthma severity and distinct immunologic pathways. Methods In healthy subjects and patients with mild-to-severe asthma, we immunostained bronchial biopsy specimens for TSLP, OX40, OX40L, TH 2 cytokines, and inflammatory cell markers. We examined gene expression using RNA microarrays and quantitative RT-PCR. Results There was considerable heterogeneity in the levels of TSLP, IL-13, and IL-4 immunostaining across the cohort of asthmatic patients examined. Overall, TSLP protein expression was significantly increased in airway epithelium and lamina propria of asthmatic patients, particularly in patients with severe asthma. TSLP immunostaining in both compartments correlated with the severity of airflow obstruction. The majority of leukocytes expressing IL-13 were possibly nuocytes. Accounting for intersubject variability, the 55% of asthmatic patients with increased IL-13 immunostaining in the lamina propria also had increased IL-4 and TSLP expression. This was further substantiated by significant correlations between TSLP gene expression, a TH 2 gene expression signature, and eosinophilic inflammation in bronchial biopsy specimens. Immunostaining for OX40, OX40L, and CD83 was sparse, with no difference between asthmatic patients and healthy subjects. Conclusion TSLP expression is increased in a subset of patients with severe asthma in spite of high-dose inhaled or oral corticosteroid therapy. Targeting TSLP might only be efficacious in the subset of asthma characterized by increased TSLP expression and TH 2 inflammation.
Lebrikizumab Treatment in Adults with Asthma Corren, Jonathan; Lemanske, Robert F; Hanania, Nicola A ...
The New England journal of medicine,
09/2011, Letnik:
365, Številka:
12
Journal Article
Recenzirano
Odprti dostop
In this trial, patients with poorly controlled asthma despite inhaled glucocorticoid therapy were treated with lebrikizumab, an anti–IL-13 monoclonal antibody. Lebrikizumab was associated with ...improvement in FEV
1
overall, with greater improvements in patients with a positive IL-13 signature.
Asthma is a complex disease with marked heterogeneity in the clinical course and in the response to treatment.
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Variability in the type of airway inflammation may underlie this heterogeneity.
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Despite treatment with inhaled glucocorticoids, many patients continue to have uncontrolled asthma that requires more intensive therapy.
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Interleukin-13, a pleiotropic cytokine of type 2 helper T cells (Th2), has been thought to contribute to many key features of asthma.
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Production of interleukin-13 is inhibited by inhaled glucocorticoids, but these agents also have many other effects on the airways. Some patients with uncontrolled asthma continue to have elevated levels of . . .
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