Ibrutinib treatment improves T cell number and function in CLL patients

J Clin Invest. 2017 Aug 1;127(8):3052-3064. doi: 10.1172/JCI89756. Epub 2017 Jul 17.

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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Aged
  • Animals
  • Antigens, CD / metabolism
  • Antineoplastic Agents / therapeutic use*
  • 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
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukocytes, Mononuclear / metabolism
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Programmed Cell Death 1 Receptor / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Pyrazines / therapeutic use
  • Pyrazoles / therapeutic use*
  • Pyrimidines / therapeutic use*
  • Receptors, Immunologic / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism*

Substances

  • Antigens, CD
  • Antineoplastic Agents
  • BTLA protein, human
  • Benzamides
  • CTLA-4 Antigen
  • IL10 protein, human
  • Immunosuppressive Agents
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Pyrazines
  • Pyrazoles
  • Pyrimidines
  • Receptors, Immunologic
  • Interleukin-10
  • ibrutinib
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Btk protein, mouse
  • acalabrutinib
  • antigens, CD200

Associated data

  • ClinicalTrials.gov/NCT01589302
  • ClinicalTrials.gov/NCT02029443