Long-term effect of Kaftrio therapy on the innate immune response of people with cystic fibrosis

Elezacaftor-tezacaftor-ivacaftor (Kaftrio) is the most effective modulator therapy for a large majority of people with cystic fibrosis (pwCF). In previous studies, we and others demonstrated that monocytes and macrophages from pwCF with at least one F508del mutation, partially improved Pseudomonas aeruginosa phagocytosis after 1-12 months of Kaftrio therapy1,2,3. In addition, the anti-inflammatory effect of Kaftrio on CF monocytes has been associated with an increase in CFTR protein expression4. In order to address the durability of Kaftrio effect on innate immune response we have analyzed the phagocytic activity and the expression of CFTR in monocytes from pwCF through 48 months of Kaftrio treatment. 53 F508del/F508del or F508del/other pwCF were enrolled in the study. Peripheral blood mononuclear cells were isolated and infected in vitro with P. aeruginosa, then phagocytosis by monocytes was evaluated by flow cytometry. CFTR expression in purified blood monocytes was assessed by qRT-PCR and Western Blot. We observed that CF monocytes maintained a significant improvement of P. aeruginosa phagocytosis through 48 months of Kaftrio therapy. CFTR protein levels significantly increased in monocytes after therapy respect to the pre-therapy samples. Differently, CFTR mRNA levels remained unchanged after therapy. These results extend the beneficial effects of Kaftrio therapy on the antimicrobial activity and CFTR expression of CF monocytes. Kaftrio therapy was associated with sustained improvement in lung function and other clinical and microbiological outcomes after four years of therapy. 1Cavinato et al., 2023 doi:10.1183/13993003.00725-2022. 2Zhang et al., 2023 doi:10.1183/13993003.02861-2021. 3Aridgides et al., 2023 doi:10.1038/s41598-023-38300-9 4Gabillard-Lefort et al., 2022 doi:10.1164/rccm.202106-1426OC