Leniolisib reduced lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity (IEI) characterized by abnormal FAS-mediated apoptosis of lymphocytes that leads to lymphoproliferation and expansion of CD4-/CD8- double-negative T cells (DNTs). In patients with ALPS-FAS, DNTs have been reported to exhibit increased activity in the phosphoinositide 3-kinase δ (PI3Kδ)/mammalian target of rapamycin (mTOR) pathway. Although mTOR inhibition with sirolimus has improved autoimmune cytopenias and organomegaly in patients with ALPS, it requires monitoring of serum levels, and common adverse events frequently hamper long-term use. As leniolisib, a selective PI3Kδ inhibitor, reduced lymphoproliferation in another IEI known as activated PI3Kδ syndrome, efficacy was examined in a murine model of ALPS. Changes in organ weight and key immune subsets in MRL/lpr-/- mice receiving vehicle or leniolisib (40 or 80 mg/kg/day) by oral gavage were assessed. Leniolisib limited the canonical features of ALPS, including lymphadenopathy, splenomegaly, and elevated DNTs, in a dose-dependent manner. These results support the evaluation of leniolisib in patients with ALPS (NCT06549114).