Disruption ofin vivoChronic Lymphocytic Leukemia Tumor–Microenvironment Interactions by Ibrutinib – Findings from an Investigator-Initiated Phase II Study

Abstract

Purpose Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B cell receptor (BCR) signaling. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. While the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment. Experimental Design Patients received single agent ibrutinib on an investigator-initiated phase 2 trial. Serial blood and tissue samples were collected pre-treatment and during treatment. Changes in cytokine levels, cellular subsets and microenvironmental interactions were assessed. Results Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Further, ibrutinib treatment decreased circulating tumor cells and overall T cell numbers. Most notably, a reduced frequency of the Th17 subset of CD4+ T cells was observed concurrent with reduced activation markers and expression of PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4+ T cells in vitro. Lastly, in the bone marrow microenvironment, we found that ibrutinib disaggregated the interactions of macrophages and CLL cells, inhibited secretion of CXCL13 and decreased the chemoattraction of CLL cells. Conclusions In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the anti-tumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL.

Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

“…Niemann et al reported decreased T-cell activation, proliferation, and PD-1 expression in patients with CLL after ibrutinib therapy. 84 Consistent with prior findings in ITK knockout mice, the authors demonstrated reduced proliferation of circulating Th17 cells in these patients and inhibition of Th17 differentiation in ex vivo assays. In addition, ibrutinib treatment disrupted CLL-macrophage interactions in bone marrow specimens.…”

Ibrutinib withdrawal symptoms in patients with Waldenström macroglobulinemia

“…However, recent data demonstrate ibrutinib induces significant suppression of inflammatory cytokines (i.e. TNFα, IL2RA and CXCL13), as well as a downregulatory effect on T-cells and macrophages [9][10][11][12]. It is possible that re-activation of both tumoral and microenvironmental cells during an ibrutinib hold could generate a cytokine release syndrome and cause the withdrawal symptoms reported here.…”

Ibrutinib responsive central nervous system involvement in chronic lymphocytic leukemia

“…Ibrutinib is the first in a class of US Food and Drug Administration (FDA)-approved Bruton tyrosine kinase inhibitor that acts by blocking B-cell antigen receptor signaling and changing the tumor microenvironment, 6 thereby reducing malignant proliferation of B cells and inducing apoptosis. [6][7][8] It is indicated in relapsed/refractory and in treatment-naïve 17p-deleted CLL.…”