Beschreibung:
<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Purpose</jats:title>
<jats:p>Acute B-lymphoblastic leukemia (B-ALL) is a malignant disease characterized by accumulation of clonal immature lymphocytes in the bone marrow and peripheral blood. The approval of BCR::ABL1 tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib and ponatinib marked a milestone in targeted therapy only for a subset of patients carrying the translocation t(9;22)(q34;q11). Immunotherapy with the bispecific antibody (bsAb) blinatumomab targeting CD19xCD3 revolutionized treatment of all B-ALL cases. The combination of both TKI and bsAb, so-called “dual targeting”, is currently under clinical investigation, although TKI might influence T cell effects.</jats:p>
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<jats:title>Methods</jats:title>
<jats:p>We here investigated the combination of different TKI and blinatumomab in BCR::ABL1<jats:sup>+</jats:sup> and BCR::ABL1<jats:sup>−</jats:sup> B-ALL cell lines and primary samples regarding T cell proliferation, differentiation, cytokine release and killing of tumor cells.</jats:p>
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<jats:title>Results</jats:title>
<jats:p>In vitro analysis revealed profound reduction of T cell proliferation, differentiation, cytokine release and killing of tumor cells upon application of BCR::ABL1 TKI with blinatumomab. Inhibition was more pronounced with dasatinib and ponatinib compared to nilotinib and imatinib. T cell signalling after CD3 stimulation was impaired by TKI mirrored by inhibition of LCK phosphorylation. This known off-target effect might influence the efficacy of bsAb therapy when combined with BCR::ABL1 TKI.</jats:p>
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<jats:title>Conclusion</jats:title>
<jats:p>In conclusion, we propose that nilotinib and imatinib might also be suitable substances for combination with blinatumomab and suggest evaluation in clinical trials.</jats:p>
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