期刊
BLOOD
卷 137, 期 7, 页码 939-944出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020005655
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- NCI NIH HHS [R01 CA065823] Funding Source: Medline
Combining blinatumomab with different ABL inhibitors in Philadelphia chromosome-positive ALL can have different effects on T-cell proliferation and IFN-gamma production, highlighting the importance of maintaining T-cell function in combination therapies.
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-gamma (IFN-gamma). The addition of the ABL inhibitors imatinib or nilotinib to blinatumomab did not inhibit T-cell proliferation or 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 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.
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