Concomitant use of a dual Src/ABL kinase inhibitor eliminates the in vitro efficacy of blinatumomab against Ph+ ALL

Blood. 2021 Feb 18;137(7):939-944. doi: 10.1182/blood.2020005655.

Abstract

Blinatumomab is currently approved for use as a single agent in relapsed and refractory acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated via signaling through the T-cell receptor (TCR). There is now much interest in combining blinatumomab with targeted therapies, particularly in Philadelphia chromosome-positive ALL (Ph+ ALL). However, some second- and third-generation ABL inhibitors also potently inhibit Src family kinases that are important in TCR signaling. We combined ABL inhibitors and dual Src/ABL inhibitors with blinatumomab in vitro from both healthy donor samples and primary samples from patients with Ph+ ALL. Blinatumomab alone led to both T-cell proliferation and elimination of target CD19+ cells and enhanced production of interferon-γ (IFN-γ). The addition of the ABL inhibitors imatinib or nilotinib to blinatumomab did not inhibit T-cell proliferation or IFN-γ production. However, the addition of dasatinib or ponatinib inhibited T-cell proliferation and IFN-γ production. Importantly, there was no loss of CD19+ cells treated with blinatumomab plus dasatinib or ponatinib in healthy samples or samples with a resistant ABL T315I mutation by dasatinib in combination with blinatumomab. These in vitro findings bring pause to the excitement of combination therapies, highlighting the importance of maintaining T-cell function with targeted therapies.

MeSH terms

  • Antibodies, Bispecific / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • B-Lymphocytes
  • Dasatinib / pharmacology
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Humans
  • Imatinib Mesylate / pharmacology
  • Imidazoles / pharmacology
  • Interferon-gamma Release Tests
  • Jurkat Cells
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Mutation, Missense
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / physiology
  • Phosphorylation / drug effects
  • Point Mutation
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Processing, Post-Translational / drug effects
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / genetics
  • Pyridazines / pharmacology
  • Pyrimidines / pharmacology
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tumor Cells, Cultured
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / physiology

Substances

  • Antibodies, Bispecific
  • Antineoplastic Agents
  • Imidazoles
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Pyridazines
  • Pyrimidines
  • Receptors, Antigen, T-Cell
  • ponatinib
  • blinatumomab
  • Imatinib Mesylate
  • ABL1 protein, human
  • Fusion Proteins, bcr-abl
  • LCK protein, human
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Proto-Oncogene Proteins c-abl
  • src-Family Kinases
  • nilotinib
  • Dasatinib