Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib

Abstract

Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1CD4 and senescent CD57CD4 T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production

“…First, this work predicts that multiple monogenic or polygenic mechanisms that similarly exaggerate PI3K activity could also trigger autoantibody formation. Hence the findings here encourage testing of specific PI3Kδ inhibitors, currently approved for treatment of some human B cell malignancies (Fruman et al, 2017;Hewett et al, 2016) and trialed for treating patients with PIK3CD GOF mutations (Rao et al, 2017), as potential targeted therapies for human antibody-mediated autoimmune diseases. Second, induction of strong PI3K signaling may be beneficial for vaccine responses where some degree of cross-reactivity with self needs to be overcome.…”

PI3Kδ hyper-activation promotes the development of B cells that exacerbateStreptococcus pneumoniaeinfection in an antibody-independent manner

“…Clinical trials are currently ongoing using both inhaled and systemic PI3Kδ inhibitors (NCT02593539, NCT02435173 and NCT02859727). Systemic use of PI3Kδ inhibitor has shown promise in reduction of lymphoproliferation and immune cell aberrations in patients with APDS, however, no comments were made regarding recurrent infections or respiratory manifestations 42 . Systemic use of PI3Kδ inhibitors in malignancies have been associated with serious side effects, including colitis 43 .…”

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

“…Treatment of patients with rapamycin or new small molecule inhibitors specifically targeting PI3K110δ leads to clinical improvement, and in the case of rapamycin, this is accompanied by partial restoration of NK cell function but no detectable change in NK cell phenotype. 162,213 It is interesting to speculate as to the source of cytolytic dysfunction in the NK cells in these patients, particularly in the context of their phenotype. While some downstream effectors of the PI3K pathway are hyperactivated in patient cells, such as AKT, the phosphorylation of ERK in NK cells is significantly decreased when compared to healthy donors.…”