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Interleukin signaling mitigates the inhibitory effects of combined Src/BCR-ABL1 blockade on T-cell activity in Philadelphia chromosome-positive acute lymphoblastic leukemia

Year: 2026
Type: article
Abstract: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), driven by the BCR-ABL1 fusion gene, remains a high-risk malignancy despite therapeutic advances. Tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 have significantly improved outcomes, but resistance and relapse persist, necessitating novel strategies such as combining TKI with bispecific T-cell engagers (BiTE) like blinatumomab. Blinatumomab redirects T cells to eliminate CD19+ leukemia cells and has shown impressive clinical activity in Ph+ ALL when combined with SrcBCR-ABL1 TKI. However, this contrasts with preclinical observations reporting that Src kinase inhibition by Src/BCR-ABL1 TKI antagonizes blinatumomab-mediated T-cell activation. Consistent with prior preclinical studies, we demonstrate that dasatinib and ponatinib, unlike SRC-sparing TKI (imatinib, nilotinib), antagonize blinatumomab's T-cell engaging efficacy by potently inhibiting LCK Y394 phosphorylation, a critical step in proximal TCR signaling. This inhibition impairs T-cell proliferation, cytokine production, and NFAT activation. To reconcile this in vitro antagonism with favorable clinical combination outcomes, we confirmed that the mechanism of SRC inhibition is T-cell intrinsic, and we explored the impact of interleukins. We show that TKI-induced T-cell suppression and antagonism can be significantly improved by supplementing co-cultures with common γ-chain cytokines, particularly IL-7. IL-7 robustly enhances human T-cell proliferation, reduces exhaustion, and significantly improves blinatumomab's cytotoxic efficacy in the presence of Src/BCR-ABL1 TKI.
DOI: 10.3324/haematol.2025.288829
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $2,157
OpenAlex ID: W7127904714
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