One size does not fit all: uncontrolled T2 inflammation on tezepelumab—a case series

Tezepelumab is the most recent human monoclonal antibody in the therapeutic arsenal of patients with severe uncontrolled asthma. It neutralizes thymic stromal lymphopoietin (TSLP). Phase 2 and phase 3 studies showed a significant reduction in asthma exacerbations in the severe asthma population, with the greatest effects seen in patients with a type 2 (T2) phenotype. TSLP is in close relation with the epithelium which is believed to be the starting point of the inflammatory cascade. Hence, blocking TSLP is expected to fully control type 2 inflammation and its actors such as interleukin 4 (IL-4), IL-13, IL-5 and eosinophils. This case report describes asthma patient cases with uncontrolled T2 inflammation on tezepelumab and explores the potential evasion mechanisms of TSLP blockage. We report four patients who developed symptomatic uncontrolled T2 inflammation following the initiation to tezepelumab. All cases were biologic-experienced and achieved best asthma control with benralizumab. Several hypotheses have been proposed to explain this phenomenon. One possibility is an immune-driven process within the spectrum of eosinophilic granulomatosis with polyangiitis (EGPA). In EGPA, eosinophils act as immunoregulatory cells and have a critical role in promoting the T2 response, which truly sanction the disease as an eosinophilic immune dysfunction disorder. With such process, targeting upstream signals, such as TSLP may prove ineffective in controlling the self-sustained eosinophilic process. Additionally, local airway immunity, even in the absence of EGPA, could influence the suboptimal response to anti-TSLP therapy by exacerbating the in situ T2 response. Tezepelumab is not the optimal treatment for all asthma patients requiring biologic therapy. A non-epithelial derived source of inflammation might explain the suboptimal response. These cases stress the importance of phenotyping and individualisation of therapy as essential steps of the severe asthma care.