Concomitant use of a dual Src/ABL kinase inhibitor eliminates the in vitro efficacy of blinatumomab against Ph+ ALL.
Blood
; 137(7): 939-944, 2021 02 18.
Article
en En
| MEDLINE
| ID: mdl-32898857
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Activación de Linfocitos
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Linfocitos T
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Proteínas Proto-Oncogénicas c-abl
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Proteínas de Fusión bcr-abl
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Anticuerpos Biespecíficos
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Familia-src Quinasas
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Inhibidores de Proteínas Quinasas
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Leucemia-Linfoma Linfoblástico de Células Precursoras
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Proteínas de Neoplasias
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Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Blood
Año:
2021
Tipo del documento:
Article