A crucial role is played by TSLP in driving dendritic cell-induced polarization of Th2 lymphocytes [ 61 ]. When purified from patients with allergic asthma, myeloid dendritic cells can be primed to induce Th2 cell expansion by a combination of TSLP and dermatophagoides pteronyssinus-derived allergens [ 64 ].
A further contribution to the pathobiology of T2-high asthma is provided by other cellular elements releasing IL-4 such as T follicular helper cells Tfh , whose differentiation in lung-draining lymph nodes is dependent on OX40L-positive dendritic cells activated by TSLP [ 66 ]. In patients with allergic asthma, induction of type 2 airway inflammation mediated by TSLP is further potentiated by its negative impact on the immunomodulatory action of lung T regulatory Treg lymphocytes [ 70 ].
In particular, TSLP inhibits the production of the anti-inflammatory cytokine interleukin IL by Treg lymphocytes, thus impairing the suppressive effects exerted by these cells on allergic proinflammatory pathways [ 70 ].
In addition to being implicated in the pathobiology of type 2 airway inflammation, TSLP appears to be involved in T2-low neutrophilic asthma, characterized by a pivotal pathogenic role played by Th17 lymphocytes [ 71 ].
Hence, such findings suggest that in asthmatic airways TSLP plays a pivotal role in promoting structural changes via a crosstalk occurring between inflammatory and resident cells, the latter including epithelial cells, fibroblasts, and smooth muscle cells.
Initially tested in patients with mild allergic asthma, tezepelumab was shown to be capable of inhibiting several effects induced by an allergen challenge [ 79 ].
In particular, 31 enrolled patients were randomly assigned to receive either a placebo or three-monthly injections of tezepelumab, administered via the intravenous route at the dosage of mg. When compared to placebo, tezepelumab prevented allergen-dependent bronchoconstriction, as documented on days 42 and 84 by This drug did not elicit any change in total serum levels of IgE.
No serious adverse events were reported during this study [ 79 ]. Subsequently, the randomized, double-blind, placebo-controlled, multicenter PATHWAY phase 2b trial was carried out between December and March at sites throughout 12 countries [ 80 ].
Furthermore, recruitable patients were also characterized by a history of either at least two asthma exacerbations or at least one severe asthma exacerbation leading to hospitalization, occurring during the 12 months preceding enrolment. An exacerbation not requiring hospitalization was defined as a worsening of asthma symptoms needing further treatment for at least 3 days with systemic corticosteroids, regardless of the necessity of an emergency room visit.
Uncontrolled asthma was also documented by a score of at least 1. Subjects with clinically relevant respiratory diseases other than asthma were excluded from the study. Among screened patients, were randomly subdivided into four groups including a placebo arm of subjects, and three subgroups of patients receiving subcutaneous injections of tezepelumab every 4 weeks, at dosages of 70 mg low dose: patients , mg medium dose: patients , or mg high dose: patients.
The primary goal of the study was to assess at week 52 the effects of tezepelumab on the annualized asthma exacerbation rate AAER. This very relevant impact of tezepelumab on AAER was found to be independent of baseline blood eosinophil counts [ 80 ]. Moreover, a recent post hoc analysis of the PATHWAY trial showed that at the dosage of mg, tezepelumab decreased AAER to a similar extent in severe uncontrolled asthmatic patients, with or without nasal polyposis [ 81 ].
Another post-hoc analysis also demonstrated that tezepelumab lowered asthma exacerbations across all four seasons of the year [ 82 ]. Tezepelumab also prolonged the time to the first asthma exacerbation. Furthermore, when considering the secondary outcomes, after 52 weeks of treatment tezepelumab significantly improved the ACQ-6 score in all three interventional subgroups.
Tezepelumab also incremented pre-bronchodilator FEV 1 by , , and mL in the low-dose, medium-dose, and high-dose groups, respectively [ 80 ]. In addition, in all tezepelumab subgroups this biologic drug significantly and persistently down-regulated key biomarkers of type 2 asthma such as blood eosinophil numbers, FeNO levels, and total serum IgE concentrations [ 80 ].
However, the remarkable preventive action exerted by tezepelumab on asthma exacerbations occurred regardless of baseline levels of blood eosinophils or other indicators of T2-high inflammation [ 80 ], and this result can undoubtedly represent a relevant advantage for tezepelumab with respect to most of the currently approved anti-asthma biologics. With regard to safety and tolerability, the overall occurrence of adverse events, mainly including nasopharyngitis, bronchitis, and headache, was similar across the four study groups [ 80 ].
Indeed, Because of the occurrence of adverse events, the trial was discontinued by one patient treated with placebo, as well as by two and three recipients of the medium and high doses of tezepelumab, respectively. Similar rates of skin reactions at the level of the injection site were reported by patients undergoing treatment with either the placebo or tezepelumab.
No anaphylactic reactions were reported. Anti-drug antibodies were detected in 8. No neutralizing antibodies were found. NAVIGATOR is a multicenter, placebo-controlled, double-blind and randomized trial, recruiting more than adults 18—80 years old and adolescents 12—17 years with severe asthma not adequately controlled by medium-to-high dosages of ICS, associated with at least another controller drug [ 83 ].
Once again, the primary endpoint is prevention of AAER [ 84 ]. Secondary outcomes include the therapeutic effects of tezepelumab on asthma control, health-related quality of life, and lung function [ 84 ]. Preliminary results suggest that tezepelumab, administered subcutaneously at the dosage of mg every 4 weeks, was able to achieve the primary goal of lowering AAER at week 52 [ 83 ].
The primary aim of this study is to evaluate the eventual OCS-sparing action of tezepelumab, injected subcutaneously at the dosage of mg every 4 weeks [ 85 ].
The objective of this study is very important, given the widespread use of OCS among patients with severe asthma, who are thus exposed to the risk of developing the relevant systemic adverse effects of these drugs infections, hypertension, diabetes, gastrointestinal complications, osteoporosis, bone fracture, glaucoma, cataract, reduced growth in children and adolescents, adrenal insufficiency, and psychiatric disorders [ 86 ].
Finally, CASCADE is a phase 2, double-blind, randomized and placebo-controlled study, focusing on the anti-inflammatory activity of tezepelumab [ 88 ]. Here, patients with uncontrolled, moderate-to-severe asthma, undergoing treatment with mg of tezepelumab administered subcutaneously every 4 weeks for 28 weeks, will be monitored throughout this study period [ 88 ]. Asthmatic subjects will be enrolled regardless of their baseline eosinophilic inflammatory pattern.
With respect to baseline, the CASCADE trial aims to evaluate the potential inflammatory changes induced by the biological therapy with tezepelumab. In particular, bronchoscopic biopsies will be examined in order to assess the eventual differences occurring between baseline and week 28 with regard to airway submucosal infiltration by eosinophils, neutrophils, T lymphocytes, and mast cells [ 88 ].
Moreover, the possible anti-remodeling action of tezepelumab will be explored by measuring the reticular basement membrane thickening before and after treatment with tezepelumab. TSLP represents one of the most suitable therapeutic targets for emerging biological treatments of severe asthma [ 89 , 90 , 91 ]. Indeed, TSLP plays a strategic role in asthma pathobiology, due to its top position located at a very upstream level within the complex network of cellular and molecular pathways leading to airway inflammation Figure 1.
In this regard, the fully human anti-TSLP monoclonal antibody tezepelumab is, so far, the most studied drug among the currently developed anti-alarmins [ 90 ]. The initial results provided by the PATHWAY trial open very promising perspectives for an eventual key role of tezepelumab in the future therapies of type 2 severe asthma. Currently, ongoing studies are essential to eventually confirm and extend such preliminary observations.
It should be very interesting to comparatively evaluate the therapeutic effects of both currently available and prospective biological treatments of severe T2-high asthma.
However, published studies refer to systematic reviews and network meta-analyses [ 92 ] rather than to direct head-to-head comparisons, which might prove to be more useful. Furthermore, the potential efficacy of tezepelumab should also be explored with regard to its possible therapeutic application in T2-low neutrophilic asthma, given the relevant contribution of TSLP to the pathophysiology of this difficult-to-treat endotype.
Lastly, because of the biologic activities exerted by TSLP on airway structural cells, current trials will probably also provide interesting information about the supposed ability of tezepelumab to modulate bronchial remodeling in severe asthma. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
National Center for Biotechnology Information , U. Int J Mol Sci. Published online Apr Find articles by Angelantonio Maglio. Find articles by Alessandro Vatrella. Nicola Scichilone, Academic Editor. Author information Article notes Copyright and License information Disclaimer. Received Mar 28; Accepted Apr This article has been cited by other articles in PMC.
Abstract Thymic stromal lymphopoietin TSLP is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in asthma by acting as an upstream activator of cellular and molecular pathways leading to type 2 T2-high airway inflammation.
Keywords: asthma, alarmins, TSLP, tezepelumab. Introduction Asthma is a chronic obstructive respiratory disease, mainly characterized by airflow limitation due to bronchial inflammation and airway remodeling [ 1 , 2 ]. Open in a separate window. Figure 1. Figure 2. Conclusions TSLP represents one of the most suitable therapeutic targets for emerging biological treatments of severe asthma [ 89 , 90 , 91 ]. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflicts of Interest The authors declare that there is no conflict of interest. References 1. Papi A.
Khalaf K. Asthma from immune pathogenesis to precision medicine. McDowell P. Different endotypes and phenotypes drive the heterogeneity in severe asthma. Suraya R. Molecular mechanism of asthma and its novel molecular target therapeutic agent. Pelaia C. Tran T. Overlap of atopic, eosinophilic, and TH2-high asthma phenotypes in a general population with current asthma. Allergy Asthma Immunol. Nelson R. Eosinophilic Asthma. Allergy Clin.
Other Outcome Measures: Change in diversity in airway microbiota in patients treated with MEDI compared to placebo [ Time Frame: 12 weeks ] Diversity of airway microbiota as measured by 16S gene sequencing in BAL measured at baseline and after the week treatment period.
Relative abundances of airway microbiota as measured by 16S gene sequencing in BAL measured at baseline and after the week treatment period. Level of FeNO ppb before and after weeks treatment between groups. Number of ILC2 in peripheral blood measured at baseline and after the week treatment period between groups. ACQ-score measured at baseline and after the week treatment period between groups.
FEV1 post beta2 measured at baseline and after the week treatment period. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision.
A diagnosis of asthma as defined by GINA ginasthma. Previous medical history or evidence of an uncontrolled intercurrent illness. Clinically relevant abnormal findings in hematology or clinical chemistry. Evidence of active liver disease. History of cancer. Acute upper or lower respiratory infections. Helminth parasitic infection. Known history of active tuberculosis TB. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology.
A positive human immunodeficiency virus HIV test. History of sensitivity to any component of the investigational product. History of anaphylaxis to any biologic therapy. History of documented immune complex disease Type III hypersensitivity reactions to mAb administration. History of any known primary immunodeficiency disorder. Oral corticosteroids. Use of 5-lipoxygenase inhibitors. Use of immunosuppressive medication.
Pregnant, breastfeeding or lactating females. History of chronic alcohol or drug abuse. Receipt of the Th2 cytokine inhibitor suplatast Receipt of any live or attenuated vaccines.
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Federal Government. Read our disclaimer for details. Results First Posted : May 6, Last Update Posted : May 6, Study Description. Detailed Description:. FDA Resources. Arms and Interventions. Cat immunotherapy will be administered weekly. AMG will be administered once every 4 weeks at dose of mg intravenously. Each AMG dose will be administered at least 1 day before immunotherapy through week 24, then on the same day as immunotherapy thereafter. A standardized allergen extract licensed in the United States for allergen immunotherapy, and is formulated as a long-acting suspension for subcutaneous injection.
AMG will be administered every four weeks. Placebo for allergen-specific immunotherapy administered subcutaneously.
Outcome Measures. Participants indicate a score on each subscale of 0, 1, 2, or 3, indicating none, mild, moderate, or severe symptoms, respectively. Higher scores indicate more severe nasal symptoms. The model included fixed effects for treatment, time, and treatment by time interaction and included covariates for site, baseline TNSS AUC and Baseline Cat exposure low vs high.
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