Rao V Koneti, Webster Sharon, Dalm Virgil A S H, Šedivá Anna, van Hagen P Martin, Holland Steven, Rosenzweig Sergio D, Christ Andreas D, Sloth Birgitte, Cabanski Maciej, Joshi Aniket D, de Buck Stefan, Doucet Julie, Guerini Danilo, Kalis Christoph, Pylvaenaeinen Ilona, Soldermann Nicolas, Kashyap Anuj, Uzel Gulbu, Lenardo Michael J, Patel Dhavalkumar D, Lucas Carrie L, Burkhart Christoph
National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
Department of Internal Medicine and.
Blood. 2017 Nov 23;130(21):2307-2316. doi: 10.1182/blood-2017-08-801191. Epub 2017 Sep 29.
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.
编码磷酸肌醇 3-激酶δ（PI3Kδ）的基因中的致病性功能获得性变异会导致过渡性 B 细胞和衰老 T 细胞的积累、淋巴结病和免疫缺陷（活化 PI3Kδ综合征[APDS]）。了解 APDS 的遗传病因使我们有机会探索将 PI3Kδ抑制作为一种精准医学疗法。在此，我们报告了在 APDS 中抑制 PI3Kδ的体外和体内效应。使用选择性 PI3Kδ抑制剂来那度胺（CDZ173）进行治疗，在异位表达导致 APDS 的 p110δ变体的细胞系以及来自患者的 T 细胞母细胞中，引起了 PI3Kδ通路过度激活的剂量依赖性抑制（以 AKT/S6 的磷酸化来衡量）。对 6 名 APDS 患者进行了一项临床试验，该试验为一项为期 12 周的开放标签、多中心、受试者内剂量递增研究，口服来那度胺以评估安全性、药代动力学以及对淋巴细胞增殖和免疫失调的影响。口服来那度胺导致离体评估的 PI3K/AKT 通路活性出现剂量依赖性降低，并改善了免疫失调。我们观察到来那度胺治疗使循环中的过渡性和幼稚 B 细胞恢复正常，PD-1⁺CD4⁺和衰老 CD57⁺CD4⁺T 细胞减少，血清免疫球蛋白 M 以及包括干扰素γ、肿瘤坏死因子、CXCL13 和 CXCL10 在内的炎症标志物水平降低。治疗 12 周后，所有患者的淋巴细胞增殖均有所改善，淋巴结大小和脾脏体积分别缩小了 39%（平均值；范围为 26% - 57%）和 40%（平均值；范围为 13% - 65%）。因此，来那度胺耐受性良好，并改善了 APDS 的实验室和临床参数，支持将 PI3Kδ的特异性抑制作为 APDS 和其他以 PI3Kδ通路过度激活为特征的疾病的一种有前景的新靶向治疗方法。该试验已在 www.clinicaltrials.gov 上注册，注册号为#NCT02435173。
