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

Authors
  • Leonard, Jessica1
  • Kosaka, Yoko2
  • Malla, Pavani1
  • LaTocha, Dorian3
  • Lamble, Adam4
  • Hayes-Lattin, Brandon5
  • Byrd, Kaelan Hunter2
  • Druker, Brian J2
  • Tyner, Jeffrey W3
  • Chang, Bill H6
  • Lind, Evan F2
  • 1 Oregon Health Sciences, Portland, Oregon, United States. , (United States)
  • 2 Oregon Health & Science University, Portland, Oregon, United States. , (United States)
  • 3 Oregon Health and Science University, Portland, Oregon, United States. , (United States)
  • 4 Seattle Children's Hospital, Seattle, Washington, United States. , (United States)
  • 5 OHSU Knight Cancer Institute, Portland, Oregon, United States. , (United States)
  • 6 OHSU, Portland, Oregon, United States. , (United States)
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Sep 08, 2020
Identifiers
DOI: 10.1182/blood.2020005655
PMID: 32898857
Source
Medline
Language
English
License
Unknown

Abstract

Blinatumomab is currently approved for use as a single agent in relapsed and refractory Acute Lymphoblastic Leukemia. 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 ABL/Src inhibitors with blinatumomab in vitro from both healthy donor samples as well as in primary samples from patients with Ph+ALL. Blinatumomab alone led to both T-cell proliferation and elimination of target CD19+ cells, as well as enhanced production of IFN-gamma. The addition of the ABL inhibitors imatinib or nilotinib to blinatumomab did not inhibit T-cell proliferation nor IFN-gamma production. However, the addition of dasatinib or ponatinib inhibited T-cell proliferation and IFN-gamma production. Importantly, there was no loss of CD19+ cells treated with blinatumomab plus dasatinib or ponatinib in healthy samples as well as 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. Copyright © 2020 American Society of Hematology.

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