Ibrutinib treatment improves T cell number and function in CLL patients
Meixiao Long, … , Natarajan Muthusamy, John C. Byrd
Meixiao Long, … , Natarajan Muthusamy, John C. Byrd
Published July 17, 2017
Citation Information: J Clin Invest. 2017;127(8):3052-3064. https://doi.org/10.1172/JCI89756.
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Clinical Medicine Hematology

Ibrutinib treatment improves T cell number and function in CLL patients

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. 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.

Authors

Meixiao Long, Kyle Beckwith, Priscilla Do, Bethany L. Mundy, Amber Gordon, Amy M. Lehman, Kami J. Maddocks, Carolyn Cheney, Jeffrey A. Jones, Joseph M. Flynn, Leslie A. Andritsos, Farrukh Awan, Joseph A. Fraietta, Carl H. June, Marcela V. Maus, Jennifer A. Woyach, Michael A. Caligiuri, Amy J. Johnson, Natarajan Muthusamy, John C. Byrd

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Figure 1

Ibrutinib but not acalabrutinib treatment of CLL patients increases total T cell numbers.

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Ibrutinib but not acalabrutinib treatment of CLL patients increases tota...
(A) Absolute numbers of CD8+ (upper panel) and CD4+ (lower panel) T cells before and during ibrutinib treatment (n = 18). (B) Absolute numbers of CD8+ (upper panel) and CD4+ (lower panel) T cells before and during acalabrutinib treatment (n = 12). Each cycle is 4 weeks. Cycle 3 indicates samples obtained after 2 cycles (8 weeks into treatment), and cycle 6 indicates samples obtained after 5 cycles (20 weeks into treatment). T cells were differentiated into subsets based on expression of CCR7 and CD45RA: naive T cells (CCR7+CD45RA+), central memory T cells (CCR7+CD45RA–), effector memory T cells (CCR7–CD45RA–), and more differentiated effector memory T cells (T-EMRA; CCR7–CD45RA+). Differences were assessed using linear mixed-effects models. NS, not significant.