TY - JOUR
T1 - Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib - findings from an investigator initiated phase 2 study
AU - Niemann, Carsten U
AU - Herman, Sarah E M
AU - Maric, Irina
AU - Gomez-Rodriguez, Julio
AU - Biancotto, Angelique
AU - Chang, Betty Y
AU - Martyr, Sabrina
AU - Stetler-Stevenson, Maryalice
AU - Yuan, Constance M
AU - Calvo, Katherine R
AU - Braylan, Raul C
AU - Valdez, Janet
AU - Lee, Yuh Shan
AU - Jones, Jade
AU - Wong, Deanna H
AU - Sun, Clare
AU - Marti, Gerald E
AU - Farooqui, Mohammed Z H
AU - Wiestner, Adrian
N1 - Copyright © 2015, American Association for Cancer Research.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
U2 - 10.1158/1078-0432.CCR-15-1965
DO - 10.1158/1078-0432.CCR-15-1965
M3 - Journal article
C2 - 26660519
SN - 1078-0432
VL - 22
SP - 1572
EP - 1582
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -