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.

Ibrutinib Use Complicated by Progressive Multifocal Leukoencephalopathy

“…This has been in part attributed to ibrutinib-mediated inhibition of interleukin-2 inducible kinase in T lymphocytes resulting in the potentiation of Th1 cell response and expansion of CD4+ and CD8+ cells [12,13]. This may be consistent with the increased number of both CD4+ and CD8+ T cells and a lack of functional deficits in peripheral T lymphocytes in our patient since starting ibrutinib and at the time of her last admission.…”

“…While ibrutinib has frequently been associated with an increased infection risk, it was recently reported to aug- ment humoral and cellular immunity in a subset of CLL patients [11,12]. This has been in part attributed to ibrutinib-mediated inhibition of interleukin-2 inducible kinase in T lymphocytes resulting in the potentiation of Th1 cell response and expansion of CD4+ and CD8+ cells [12,13].…”

AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

“…Through nonspecific inhibition of ITK, ibrutinib alters differentiation of T cell subsets, skews T cells from a Th2-dominant to a Th1 and CD8+ cytotoxic population [25], and blocks the secretion of cytokines from activated T cells [17]. Ibrutinib also leads to expansion of effector and effector memory T cell subsets [26]. Since this broad activity against both the neoplastic cells and the supportive microenvironment may contribute to the clinical efficacy of ibrutinib, alterations within either of these cellular compartments might also contribute to resistance.…”

Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia

“…In addition to their direct impact on tumor cells, BTK inhibitors modulate multiple cell types in the tumor microenvironment, such as tumor‐associated myeloid cells and T cells . Ibrutinib has impact on T‐cell numbers and function due to its off‐target effects on ITK, a central kinase in T‐cell receptor signaling . Furthermore, CLL development in the TCL1 model induces the accumulation of tumor‐supportive monocytes with severe skewing toward Ly6C low patrolling monocytes .…”