Disruption of in vivo Chronic Lymphocytic Leukemia Tumor-Microenvironment Interactions by Ibrutinib--Findings from an Investigator-Initiated Phase II Study

• Published in: Clinical cancer research Vol. 22; no. 7; pp. 1572 - 1582
• Main Authors: Niemann, Carsten U, Herman, Sarah E M, Maric, Irina, Gomez-Rodriguez, Julio, Biancotto, Angelique, Chang, Betty Y, Martyr, Sabrina, Stetler-Stevenson, Maryalice, Yuan, Constance M, Calvo, Katherine R, Braylan, Raul C, Valdez, Janet, Lee, Yuh Shan, Wong, Deanna H, Jones, Jade, Sun, Clare, Marti, Gerald E, Farooqui, Mohammed Z H, Wiestner, Adrian
• Format: Journal Article
• Language: English
• Published: United States 01.04.2016
• Subjects: Aged; Aged, 80 and over; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Bone Marrow - pathology; Cell Communication - drug effects; Cell Communication - immunology; Cell Differentiation - drug effects; Cell Movement - drug effects; Cell Movement - immunology; Cytokines - blood; Cytokines - metabolism; Disease Models, Animal; Female; Humans; Immunophenotyping; Inflammation Mediators - blood; Inflammation Mediators - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Middle Aged; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Th17 Cells - drug effects; Th17 Cells - immunology; Th17 Cells - metabolism; Tumor Microenvironment - drug effects
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-1965

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 tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. Although 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. Patients received single-agent ibrutinib on an investigator-initiated phase II trial. Serial blood and tissue samples were collected pretreatment and during treatment. Changes in cytokine levels, cellular subsets, and microenvironmental interactions were assessed. Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Furthermore, 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 expression of activation markers and PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4(+)T cells in vitro Finally, 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. In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the antitumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL. See related commentary by Bachireddy and Wu, p. 1547.