title: Disruption of in vivo Chronic Lymphocytic Leukemia Tumor-Microenvironment Interactions by Ibrutinib--Findings from an Investigator-Initiated Phase II Study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland. Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors.forename: Carsten U
authors.initials: CU
authors.lastname: Niemann
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Herman
authors.affiliation: Department of Laboratory Medicine, Clinical Research Center, NIH, Bethesda, Maryland.
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, Maryland.
authors.forename: Julio
authors.initials: J
authors.lastname: Gomez-Rodriguez
authors.affiliation: Center for Human Immunology, Autoimmunity and Inflammation, NIH, Bethesda, Maryland.
authors.forename: Angelique
authors.initials: A
authors.lastname: Biancotto
authors.affiliation: Pharmacyclics Inc., Sunnyvale, California.
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Chang
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Martyr
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Maryalice
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
authors.forename: Constance M
authors.initials: CM
authors.lastname: Yuan
authors.affiliation: Department of Laboratory Medicine, Clinical Research Center, NIH, Bethesda, Maryland.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Calvo
authors.affiliation: Department of Laboratory Medicine, Clinical Research Center, NIH, Bethesda, Maryland.
authors.forename: Raul C
authors.initials: RC
authors.lastname: Braylan
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Janet
authors.initials: J
authors.lastname: Valdez
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Yuh Shan
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Deanna H
authors.initials: DH
authors.lastname: Wong
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland. Medical Research Scholars Program, NIH, Bethesda, Maryland.
authors.forename: Jade
authors.initials: J
authors.lastname: Jones
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Clare
authors.initials: C
authors.lastname: Sun
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Marti
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Mohammed Z H
authors.initials: MZ
authors.lastname: Farooqui
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland. wiestnea@nhlbi.nih.gov.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001853:Bone Marrow / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D018836:Inflammation Mediators; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine