Constitutively active PI3Kδ, as occurs in patients with activated PI3K-delta syndrome (APDS) 1, results in disturbed immune cell development and function leading to microbial susceptibility and immune dysregulation. Leniolisib, a novel, orally FDA-approved bioavailable small molecule inhibitor, was engineered to selectively target PI3Kδ signaling. Leniolisib was shown to partially reconstitute lymphocyte subsets and decrease lymphoproliferation as measured by reduced spleen size and lymphadenopathy. However, its effect in other immune dysregulation manifestations has not been studied.
We evaluated the patient’s peripheral blood by flow cytometry and kidney biopsies by spatial single-cell transcriptomics and proteomics to track LN progression during treatment with leniolisib.
The patient presented at age 10 yo with recurrent sinopulmonary infections and significant bronchiectasis. She developed class IV LN at age 14 yo with autoantibodies to dsDNA, RNP, SSA, and Smith. She was treated with corticosteroids, cyclophosphamide, mycophenolate, hydroxychloroquine, and tacrolimus with suboptimal renal response and infectious complications. She was also treated with rituximab, but early B cell repopulation (with plasmablast skewing) persisted with LN flares. The frequency of her peripheral CD21lo B cells, plasmablasts, CD8 T effector memory, exhausted (PD1+), and senescent (CD57hi) cell subpopulations decreased after three doses of rituximab, with some clinical improvement in renal function, but remained clinically tenuous. She started leniolisib in April 2023, three years after her initial renal biopsy, with marked improvement and weaning of immunomodulation. Multiplexed ion beam imaging (MIBI) demonstrated that the CD45+ leukocytes in the patient’s kidney biopsy had a significant increase in the CD8 T cells and M1 macrophages compared with other 30 cLN patients’ biopsies, based on single-cell antibody panel in situ immune profiling. These data were further confirmed by spatial transcriptomic data. These tissue-specific findings are consistent with the genetic immunopathology of the patient, particularly the increased CD8 T cellular effector phenotype, which drives the immune infiltrate and renal disease in the APDS patient.
This report illustrates the criticality of understanding the underlying disease mechanism to guide pathway and patient specific therapy in autoimmunity. Further, it demonstrates the therapeutic effect leniolisib for the treatment of APDS-related immune dysregulation complications beyond splenomegaly and lymphadenopathy.
