What place will tezepelumab hold in the treatment paradigm in chronic rhinosinusitis?

Figures & data

Figure 1. Inflammatory T2 pathway and mechanisms of action of Tezepelumab during chronic rhinosinusitis (CRS) and during chronic rhinosinusitis with nasal polyps (CRSwNP).

Note: Left side: Biological mechanisms involved during CRS in a non-polyp area and monoclonal thymic stromal lymphopoietin (TSLP) antibody effects. The production of TSLP can be triggered by endogenous or external signals such as viruses, fungi (i.e. aspergillus) through the Toll Like Receptor type 2 (TLR2), proteases (House Dust Mite, Alternaria), and particulate matter. TSLP promotes T2 inflammation through its receptor, TSLPR, expressed by DCs, ILC2, mast cells, eosinophils, and also fibroblasts and results in the induction of Th2 differentiation. IL-13 and IL-4 through the IL-4 Rα can act on airway epithelium and induce mucins production and activation of macrophages. Prostaglandin D2 (PGD2) causes further recruitment of ILC2s and TH2 cells by acting on CRTH2. IL-5 acts on eosinophils via IL-5 R and induce their recruitment and activation. Tezepelumab directly binds TSLP, avoiding the interaction of the alarmin with the target cells. Blocking TSLP decreased the interleukins (IL) 4, 5 and 13 release. Right side: Hypothetical mechanism of polyp growth: Reprogramming of susceptible basal cells by T2 environment during eosinophilic CRSwNP. Polyps are composed by basal cells. In polyp, TSLP expression is uniquely restricted to basal cells in airway epithelium. IL-4/IL-13 axis: Because epigenetic changes persist in dividing cells, T2 environment in susceptible basal cells cause stable alterations in the cell phenotype. Basal cell differentiation is intrinsically impaired through the chronic IL-4/IL-13 exposure.

ALOX15 axis: ALOX15 (15-LO) produces a variety of proinflammatory lipid metabolites, notably catalyses the conversion of arachidonic acid to 15-hydroxyeicosatetraenoic acid (15-HETE), eotaxin-3, and eoxins. Eotaxin-3 plays a key role in the recruitment of eosinophils and is elevated in polyps. ALOX15 is mainly expressed in polyps, especially in basal cells and is inducible by IL-4 and IL-13.

Cystatins & P-glycoprotein axis: CST1 and CST2 are profoundly and focally overexpressed within nasal polyp epithelium, secreted in exosomes. Stimulation by TSLP induces CST1 in nasal epithelial cells and can reciprocally stimulate TSLP expression in combination with double-stranded DNA and IL-4, thereby forming a proinflammatory feedback loop. CST1 enhanced eosinophil activation and recruitment through induction of IL-5 by airway epithelial cells. TSLP stimulates degranulation of eosinophils, release of eosinophil eosinophilic cationic protein (ECP) and the formation of eosinophil extracellular traps (EETs) Table 1.

Table 1. Indirect evidence for TEZEPELUMAB efficacy in patients with CRSwNP.

Study	Patient’s profile	Findings
CASCADE [11]	18–75 years old Asthma medium-dose or high-dose inhaled corticosteroids with or without maintenance oral corticosteroids	Reductions in eosinophilic airway inflammation Reduced airway hyper-responsiveness to mannitol
CATNIP [12]	18–65 years old moderate to severe cat-induced allergic rhinitis positive skin prick test (SPT) to cat extract	Tezepelumab: augments the efficacy of SCIT during therapy, may promote tolerance after a 1-year course of treatment.
NAVIGATOR [13]	12 to 80 years old uncontrolled asthma despite medium- or high-dose inhaled glucocorticoids With or without oral glucocorticoids maintenance History of at least two asthma exacerbations (or one severe) in the past year	Post-hoc analysis [14]: Reduced AAER by 86% in NP+ (95% CI: 70–93) and 52% in NP- (95% CI: 42–61) Reduced SNOT-22 in NP+ patients by −20.10 points versus −10.55 with placebo (LSM −9.6, 95% CI: −18.2 to −0.9) NB : 83/1059 NP+ (declarative)

Note: ACQ-6 : Asthma Control Questionnaire ; AAER :Annualized Asthma Exacerbation Rate ; NP+ : Patients with nasal polyps ; NP- : Patients without nasal polyps.

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