Combination Therapy for Treating Advanced Drug-Resistant Acute Lymphoblastic Leukemia

Cancer Immunol Res. 2019 Jul;7(7):1106-1119. doi: 10.1158/2326-6066.CIR-19-0058. Epub 2019 May 28.

Abstract

Drug-resistant acute lymphoblastic leukemia (ALL) patients do not respond to standard chemotherapy, and an urgent need exists to develop new treatment strategies. Our study exploited the presence of B-cell activating factor receptor (BAFF-R) on the surface of drug-resistant B-ALL cells as a therapeutic target. We used anti-BAFF-R (VAY736), optimized for natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), to kill drug-resistant ALL cells. VAY736 antibody and NK cell treatments significantly decreased ALL disease burden and provided survival benefit in vivo However, if the disease was advanced, the ADCC efficacy of NK cells was inhibited by microenvironmental transforming growth factor-beta (TGFβ). Inhibiting TGFβ signaling in NK cells using the TGFβ receptor 1 (R1) inhibitor (EW-7197) significantly enhanced VAY736-induced NK cell-mediated ALL killing. Our results highlight the potential of using a combination of VAY736 antibody with EW-7197 to treat advance-stage, drug-resistant B-ALL patients.

Publication types

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

MeSH terms

  • Adult
  • Aniline Compounds / pharmacology*
  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antibody-Dependent Cell Cytotoxicity / drug effects*
  • Apoptosis
  • B-Cell Activation Factor Receptor / antagonists & inhibitors
  • Cell Proliferation
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Prognosis
  • Receptor, Transforming Growth Factor-beta Type I / antagonists & inhibitors
  • Triazoles / pharmacology*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Aniline Compounds
  • Antibodies, Monoclonal, Humanized
  • B-Cell Activation Factor Receptor
  • TNFRSF13C protein, human
  • Triazoles
  • vactosertib
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • ianalumab