Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK

Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):E966-72. doi: 10.1073/pnas.1500712112. Epub 2015 Feb 17.

Abstract

Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells and by doing so it can shift the balance between Th1 and Th2 T cells and potentially enhance antitumor immune responses. Here we report that the combination of anti-PD-L1 antibody and ibrutinib suppresses tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib. The combined effect of these two agents was also documented for models of solid tumors, such as triple negative breast cancer and colon cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was accompanied by enhanced antitumor T-cell immune responses. These preclinical results suggest that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic for the therapy not only of lymphoma but also in other hematologic malignancies and solid tumors that do not even express BTK.

Keywords: PD-1/PD-L1 blockade; ibrutinib; lymphoma; solid tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Antibodies, Neoplasm / pharmacology
  • B7-H1 Antigen
  • Cell Cycle Checkpoints / drug effects*
  • Cell Line, Tumor
  • Immunity, Cellular / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrazoles / pharmacology*
  • Pyrimidines / pharmacology*
  • Th1 Cells / immunology*
  • Th1 Cells / pathology
  • Th2 Cells / immunology*
  • Th2 Cells / pathology

Substances

  • Antibodies, Neoplasm
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • ibrutinib
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • emt protein-tyrosine kinase