D1.112 - ILC2 Expansion as a Biomarker of Suboptimal Response to Dupilumab in Severe Asthma: Findings from the PRISM Study

Innate lymphoid cells (ILCs), particularly type 2 ILCs (ILC2s), are known to play a crucial role in the type 2 inflammation network by releasing interleukin (IL)-4, IL-13, and IL-5 upon activation by epithelial-derived alarmins. However, longitudinal changes in ILCs following biologic therapy have not been extensively studied.

This prospective observational sub-analysis of the PRISM cohort included patients with severe asthma initiating dupilumab (n=13) or benralizumab (n=5). Peripheral blood and clinical data were obtained at baseline, 1 month, and 6 months, and ILC subsets were quantified by flow cytometry. Dupilumab-treated patients were classified as responders (Asthma Control Test [ACT] ≥20 at 6 months, n=9) or non-responders (ACT <20, n=3)

Dupilumab treatment significantly improved lung function (pre-BD FEV1: 60.2% to 81.8% predicted, p=0.001), asthma control (ACT: 16.4 to 21.6, p=0.006), and reduced FeNO (63.7 to 23.8 ppb, p=0.001) and total IgE (510 to 105 kU/L, p=0.002). Blood ILC2 levels significantly increased at 6 months in dupilumab-treated patients (p<0.05). Notably, this ILC2 expansion occurred exclusively in dupilumab non-responders, while responders showed stable ILC2 levels despite superior clinical improvements. Benralizumab treatment produced no significant ILC2 changes but decreased ILC1 levels between months 1 and 6.

The selective blood ILC2 expansion observed exclusively in dupilumab non-responders may suggest the existence of an alarmin-predominant subtype in which inflammation remains poorly controlled despite IL-4Rα blockade. These patients may benefit from upstream biologics targeting alarmins such as anti-TSLP therapy. Our findings highlight distinct ILC dynamics between biologics and suggest that ILC2 monitoring could guide personalized biologic selection in severe asthma.