Ibrutinib treatment improves T cell number and function in CLL patients

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3052-3064
Number of pages13
JournalJournal of Clinical Investigation
Volume127
Issue number8
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

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B-Cell Chronic Lymphocytic Leukemia
Cell Count
T-Lymphocytes
Immunosuppressive Agents
Therapeutics
TYK2 Kinase
Regulatory T-Lymphocytes
Interleukin-10
Immunotherapy
PCI 32765
Blood Cells
Cell Death
Phosphotransferases
Clinical Trials
Phenotype
Agammaglobulinaemia tyrosine kinase
acalabrutinib
emt protein-tyrosine kinase
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Long, M., Beckwith, K., Do, P., Mundy, B. L., Gordon, A., Lehman, A. M., ... Byrd, J. C. (2017). Ibrutinib treatment improves T cell number and function in CLL patients. Journal of Clinical Investigation, 127(8), 3052-3064. https://doi.org/10.1172/JCI89756

Ibrutinib treatment improves T cell number and function in CLL patients. / 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.

In: Journal of Clinical Investigation, Vol. 127, No. 8, 01.08.2017, p. 3052-3064.

Research output: Contribution to journalArticle

Long, M, Beckwith, K, Do, P, Mundy, BL, Gordon, A, Lehman, AM, Maddocks, KJ, Cheney, C, Jones, JA, Flynn, JM, Andritsos, LA, Awan, F, Fraietta, JA, June, CH, Maus, MV, Woyach, JA, Caligiuri, MA, Johnson, AJ, Muthusamy, N & Byrd, JC 2017, 'Ibrutinib treatment improves T cell number and function in CLL patients', Journal of Clinical Investigation, vol. 127, no. 8, pp. 3052-3064. https://doi.org/10.1172/JCI89756
Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM et al. Ibrutinib treatment improves T cell number and function in CLL patients. Journal of Clinical Investigation. 2017 Aug 1;127(8):3052-3064. https://doi.org/10.1172/JCI89756
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. / Ibrutinib treatment improves T cell number and function in CLL patients. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 8. pp. 3052-3064.
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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.",
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T1 - Ibrutinib treatment improves T cell number and function in CLL patients

AU - Long, Meixiao

AU - Beckwith, Kyle

AU - Do, Priscilla

AU - Mundy, Bethany L.

AU - Gordon, Amber

AU - Lehman, Amy M.

AU - Maddocks, Kami J.

AU - Cheney, Carolyn

AU - Jones, Jeffrey A.

AU - Flynn, Joseph M.

AU - Andritsos, Leslie A.

AU - Awan, Farrukh

AU - Fraietta, Joseph A.

AU - June, Carl H.

AU - Maus, Marcela V.

AU - Woyach, Jennifer A.

AU - Caligiuri, Michael A.

AU - Johnson, Amy J.

AU - Muthusamy, Natarajan

AU - Byrd, John C.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

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