Functional evaluation of CAR-T anti-CD123 from immune-mediated inflammatory diseases patients for novel pDCs-targeted immunotherapy.
Abstract
Background
CAR-T cell therapy (Chimeric Antigen Receptor T cells) is a promising approach for immune-mediated inflammatory diseases (IMIDs). Plasmacytoid dendritic cells (pDCs), which infiltrate tissues and secrete type I interferons (IFN-I), play a central early role in IMIDs and represent an attractive therapeutic target.
Objective
Given high CD123 expression on pDCs, we assessed the potential of CD123 CAR-T cells to eliminate pDCs across multiple IMIDs.
Methods
In the CARDA2I study, patients with psoriasis, hidradenitis suppurativa, systemic lupus erythematosus, or systemic sclerosis were enrolled regardless of disease severity or treatment. After peripheral blood mononuclear cells were collected for patients and healthy donors (HD), extended phenotype T cells were characterized at D0 and after 10 days of expansion (D10). CAR-T functionality was assessed by co-culture with autologous PBMCs and in BRGSF-HIS mice treated with human Flt3 ligand and imiquimod-induced psoriasis.
Results
Patient T cells showed phenotypic alterations at D0, which normalized by D10 post-expansion. Patient-derived CD123 CAR-T cells efficiently eliminated pDCs in vitro and in vivo and migrated to inflamed skin. In mice, CAR-T treatment reduced pDCs skin infiltration, restored epidermal architecture, and decreased psoriasiform inflammation.
Conclusion
Autologous T cells from IMIDs patients can generate functional CD123 CAR-T cells comparable to HD. These cells effectively deplete pDCs and improve psoriasis-like skin pathology, supporting their potential as a novel cell-based therapy in pDCs-driven IMIDs.