Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma.

Authors:
Michail S Lionakis
Michail S Lionakis
National Institutes of Health
United States
Kieron Dunleavy
Kieron Dunleavy
Center for Cancer Research
San Diego | United States
Mark Roschewski
Mark Roschewski
Center for Cancer Research
San Diego | United States
Brigitte C Widemann
Brigitte C Widemann
National Cancer Institute
Rockville | United States
John A Butman
John A Butman
National Institutes of Health
United States
Roland Schmitz
Roland Schmitz
University of Duisburg-Essen
Germany
Yandan Yang
Yandan Yang
National Institutes of Health
United States
Diane E Cole
Diane E Cole
Pharmacology and Experimental Therapeutics

Cancer Cell 2017 06 25;31(6):833-843.e5. Epub 2017 May 25.

Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. Increased aspergillosis was observed with ibrutinib monotherapy and DA-TEDDi-R. Aspergillosis was linked to BTK-dependent fungal immunity in a murine model. PCNSL is highly dependent on BCR signaling, and ibrutinib appears to enhance the efficacy of chemotherapy.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2017.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571650PMC
June 2017
17 Reads

Publication Analysis

Top Keywords

bcr signaling
12
signaling ibrutinib
12
primary cns
8
ibrutinib monotherapy
8
cns lymphoma
8
cell receptor
8
ibrutinib
7
remission da-teddi-r
4
performed proof-of-concept
4
complete remission
4
study ibrutinib
4
phase study
4
da-teddi-r increased
4
achieved complete
4
proof-of-concept phase
4
increased aspergillosis
4
altering bcr
4
mutations altering
4
monotherapy da-teddi-r
4
observed ibrutinib
4

Similar Publications

Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma.

Cancer Discov 2017 09 15;7(9):1018-1029. Epub 2017 Jun 15.

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York.

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Read More

View Article
September 2017

Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma.

Nat Med 2015 Aug 20;21(8):922-6. Epub 2015 Jul 20.

Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.

The two major subtypes of diffuse large B cell lymphoma (DLBCL)--activated B cell-like (ABC) and germinal center B cell-like (GCB)--arise by distinct mechanisms, with ABC selectively acquiring mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling. The ABC subtype has a ∼40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies. We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling. Read More

View Article
August 2015

Current Status of Bruton's Tyrosine Kinase Inhibitor Development and Use in B-Cell Malignancies.

Drugs Aging 2017 07;34(7):509-527

CLL Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.

The B-cell receptor (BCR) pathway plays an important role in the survival, proliferation and trafficking of cancer cells in a variety of B-cell malignancies. Recently, a number of agents have been developed to target various components of the BCR pathway. One such target is Bruton's tyrosine kinase (BTK), a Tec family kinase member found near the cell membrane that is involved in upstream BCR signaling. Read More

View Article
July 2017

Targeting Bruton's tyrosine kinase with ibrutinib in B-cell malignancies.

Clin Pharmacol Ther 2015 May 3;97(5):455-68. Epub 2015 Apr 3.

Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA.

The B-cell receptor signaling pathway, which is critical to the development and maturation of normal B-cells, is emerging as an attractive therapeutic target in B-cell malignancies. Ibrutinib is a potent irreversible inhibitor of Bruton's tyrosine kinase (Btk), a key kinase important for signal transduction in the B-cell receptor (BCR) pathway. In preclinical studies, ibrutinib potently bound to Btk, inhibited BCR signaling, and decreased tumor cell proliferation and survival in many B-cell malignancy models. Read More

View Article
May 2015