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Ibrutinib treatment improves T cell number and function in CLL patients.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2017 Aug 01; Vol. 127 (8), pp. 3052-3064. Date of Electronic Publication: 2017 Jul 17. - Publication Year :
- 2017
-
Abstract
- 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.<br />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.<br />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.<br />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.<br />Trial Registration: ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025.<br />Funding: The National Cancer Institute.
- Subjects :
- Adenine analogs & derivatives
Agammaglobulinaemia Tyrosine Kinase
Aged
Animals
Antigens, CD metabolism
Benzamides therapeutic use
CD4-Positive T-Lymphocytes cytology
CD8-Positive T-Lymphocytes cytology
CTLA-4 Antigen metabolism
Cohort Studies
Female
Humans
Immunosuppressive Agents therapeutic use
Immunotherapy
Interleukin-10 metabolism
Leukocytes, Mononuclear metabolism
Lymphocyte Activation
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Piperidines
Programmed Cell Death 1 Receptor metabolism
Protein-Tyrosine Kinases metabolism
Pyrazines therapeutic use
Receptors, Immunologic metabolism
T-Lymphocytes cytology
Antineoplastic Agents therapeutic use
Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Leukemia, Lymphocytic, Chronic, B-Cell metabolism
Pyrazoles therapeutic use
Pyrimidines therapeutic use
T-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 127
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 28714866
- Full Text :
- https://doi.org/10.1172/JCI89756