Investigating the benefit of selective PI3-kinase–δ (PIK3CD) inhibition for patients with immune dysregulation

Class I phosphatidylinositol 3-kinase delta (PIK3δ) is composed of two subunits, the catalytic p110δ expressed only in lymphocytes and the ubiquitously expressed regulatory p85α. Activation of this pathway by the T-cell- or B-cell receptor (TCR/BCR), or cytokine receptors, leads to the production of phosphatidylinositol-3,4,5-trisphosphate (PIP3), phosphorylation of AKT, activation of mTORC1 and subsequent phosphorylation of the ribosomal S6 protein. This leads to protein synthesis and improved cell survival, proliferation and migration.

Humans may carry mutations in either of the two genes encoding the two subunits: PIK3CD encoding p110δ and PIK3R1 encoding p85α, leading to Activated p110δ Syndromes (APDS). Patients show a constitutive activation of the pathway, leading to an immune dysregulation syndrome. Pharmaceutical companies have succeeded to develop a PIK3δ-specific inhibitor (leniolisib) to treat patients with APDS.

Our lead question for this research project is: Could the specific PIK3δ inhibitor – leniolisib – be useful for other patients than APDS?

With financial support of the company Pharming, we are screening different patients with common variable immunodeficiency (CVID) with or without an identified mutation for the activation level of PIK3δ by analysing the phosphorylation of AKT, S6, and FOXO in T cell blasts. On the one hand, for the patients with a known mutation, we expect to see a specific pattern of PIK3δ activation and perhaps determine if these specific patients could benefit from leniolisib treatment. On the other hand, for the patients with an unknown cause of CVID, we expect to determine on a case-by-case basis whether the patient may benefit from PIK3δ inhibition.