The Journal of clinical investigation · 2017
Ibrutinib treatment improves T cell number and function in CLL patients.
Клиническое исследование I фазыКлиническое исследование II фазыСтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Long Meixiao, Beckwith Kyle, Do Priscilla, Mundy Bethany L, Gordon Amber, Lehman Amy M, Maddocks Kami J, Cheney Carolyn, Jones Jeffrey A, Flynn Joseph M, Andritsos Leslie A, Awan Farrukh, Fraietta Joseph A, June Carl H, Maus Marcela V, Woyach Jennifer A, Caligiuri Michael A, Johnson Amy J, Muthusamy Natarajan, Byrd John C
Аннотация
BACKGROUND: Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies.
METHODS: Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated.
RESULTS: Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4+ T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells.
CONCLUSIONS: Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025.
FUNDING: The National Cancer Institute.
METHODS: Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated.
RESULTS: Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4+ T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells.
CONCLUSIONS: Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025.
FUNDING: The National Cancer Institute.
Предметные рубрики MeSH
AdenineAgammaglobulinaemia Tyrosine KinaseAgedAnimalsAntigens, CDAntineoplastic AgentsBenzamidesCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCTLA-4 AntigenCohort StudiesFemaleHumansImmunosuppressive AgentsImmunotherapyInterleukin-10Leukemia, Lymphocytic, Chronic, B-CellLeukocytes, MononuclearLymphocyte ActivationMaleMiceMice, Inbred C57BLMice, TransgenicMiddle AgedPiperidinesProgrammed Cell Death 1 ReceptorProtein-Tyrosine KinasesPyrazinesPyrazolesPyrimidinesReceptors, ImmunologicT-Lymphocytes