Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib

VK. Rao, S. Webster, VASH. Dalm, A. Šedivá, PM. van Hagen, S. Holland, SD. Rosenzweig, AD. Christ, B. Sloth, M. Cabanski, AD. Joshi, S. de Buck, J. Doucet, D. Guerini, C. Kalis, I. Pylvaenaeinen, N. Soldermann, A. Kashyap, G. Uzel, MJ. Lenardo,...

. 2017 ; 130 (21) : 2307-2316. [pub] 20170929

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Intramural

Perzistentní odkaz   https://www.medvik.cz/link/bmc18016308

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-1+CD4+ and senescent CD57+CD4- 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.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc18016308
003      
CZ-PrNML
005      
20180517141726.0
007      
ta
008      
180515s2017 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1182/blood-2017-08-801191 $2 doi
035    __
$a (PubMed)28972011
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Rao, V Koneti $u National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
245    10
$a Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib / $c VK. Rao, S. Webster, VASH. Dalm, A. Šedivá, PM. van Hagen, S. Holland, SD. Rosenzweig, AD. Christ, B. Sloth, M. Cabanski, AD. Joshi, S. de Buck, J. Doucet, D. Guerini, C. Kalis, I. Pylvaenaeinen, N. Soldermann, A. Kashyap, G. Uzel, MJ. Lenardo, DD. Patel, CL. Lucas, C. Burkhart,
520    9_
$a 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-1+CD4+ and senescent CD57+CD4- 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.
650    _2
$a zvířata $7 D000818
650    _2
$a chemokiny $x krev $7 D018925
650    _2
$a dítě $7 D002648
650    _2
$a předškolní dítě $7 D002675
650    _2
$a fosfatidylinositol-3-kinasy třídy I $x antagonisté a inhibitory $x imunologie $x metabolismus $7 D058534
650    _2
$a demografie $7 D003710
650    _2
$a vztah mezi dávkou a účinkem léčiva $7 D004305
650    _2
$a ženské pohlaví $7 D005260
650    _2
$a lidé $7 D006801
650    _2
$a imunoglobulin M $x krev $7 D007075
650    _2
$a syndromy imunologické nedostatečnosti $x farmakoterapie $x enzymologie $x imunologie $x patologie $7 D007153
650    _2
$a kojenec $7 D007223
650    _2
$a lymfatické uzliny $x účinky léků $x patologie $7 D008198
650    _2
$a aktivace lymfocytů $x účinky léků $7 D008213
650    _2
$a mužské pohlaví $7 D008297
650    12
$a cílená molekulární terapie $7 D058990
650    _2
$a mutace $x genetika $7 D009154
650    _2
$a velikost orgánu $7 D009929
650    _2
$a fenotyp $7 D010641
650    _2
$a inhibitory proteinkinas $x farmakologie $7 D047428
650    _2
$a pyridiny $x farmakokinetika $x farmakologie $7 D011725
650    _2
$a pyrimidiny $x farmakokinetika $x farmakologie $7 D011743
650    _2
$a krysa rodu Rattus $7 D051381
650    _2
$a slezina $x účinky léků $x patologie $7 D013154
650    _2
$a T-lymfocyty $x účinky léků $x imunologie $7 D013601
650    _2
$a TOR serin-threoninkinasy $x antagonisté a inhibitory $x metabolismus $7 D058570
650    _2
$a transfekce $7 D014162
655    _2
$a časopisecké články $7 D016428
655    _2
$a Research Support, N.I.H., Intramural $7 D052060
700    1_
$a Webster, Sharon $u National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
700    1_
$a Dalm, Virgil A S H $u Department of Internal Medicine and. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
700    1_
$a Šedivá, Anna $u Department of Immunology, Motol University Hospital, Prague, Czech Republic.
700    1_
$a van Hagen, P Martin $u Department of Internal Medicine and. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
700    1_
$a Holland, Steven $u National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
700    1_
$a Rosenzweig, Sergio D $u NIH Clinical Center, Bethesda, MD.
700    1_
$a Christ, Andreas D $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
700    1_
$a Sloth, Birgitte $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
700    1_
$a Cabanski, Maciej $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
700    1_
$a Joshi, Aniket D $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and. Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, MA.
700    1_
$a de Buck, Stefan $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
700    1_
$a Doucet, Julie $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
700    1_
$a Guerini, Danilo $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
700    1_
$a Kalis, Christoph $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
700    1_
$a Pylvaenaeinen, Ilona $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
700    1_
$a Soldermann, Nicolas $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
700    1_
$a Kashyap, Anuj $u National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
700    1_
$a Uzel, Gulbu $u National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
700    1_
$a Lenardo, Michael J $u National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
700    1_
$a Patel, Dhavalkumar D $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
700    1_
$a Lucas, Carrie L $u National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
700    1_
$a Burkhart, Christoph $u Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; and.
773    0_
$w MED00000807 $t Blood $x 1528-0020 $g Roč. 130, č. 21 (2017), s. 2307-2316
856    41
$u https://pubmed.ncbi.nlm.nih.gov/28972011 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20180515 $b ABA008
991    __
$a 20180517141903 $b ABA008
999    __
$a ok $b bmc $g 1299932 $s 1013148
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2017 $b 130 $c 21 $d 2307-2316 $e 20170929 $i 1528-0020 $m Blood $n Blood $x MED00000807
LZP    __
$a Pubmed-20180515

Najít záznam

Citační ukazatele

Možnosti archivace