ArticleJournal for immunotherapy of cancer2021
Src/lck inhibitor dasatinib reversibly switches off cytokine release and T cell cytotoxicity following stimulation with T cell bispecific antibodies.
Article in Journal for immunotherapy of cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 40 citations in OpenAlex.
- Dose escalation study of the HLA-A2-WT1 CD3 bispecific antibody RO7283420 in relapsed/refractory acute myeloid leukemia.Blood neoplasia · 2025Trial
- Dasatinib reversibly disrupts T cell motility and activation in lymph nodes.Science advances · 2026Article
- Transient prophylactic immunosuppression with abatacept or dasatinib prevents immune responses in AAV gene transfer.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Discovery of potent kinase inhibitors with improved pharmacokinetics and safety potentials through structural optimization of dasatinib.Communications medicine · 2026Article
- Identifying ICAM-1 as a Therapeutic Target for Cytokine Storm in Human Macrophages Through Integrative Bioinformatics Approaches.Molecules (Basel, Switzerland) · 2026Article
- From monoclonals to bispecific T cell engagers: the evolving antibody-based therapy landscape in acute myeloid leukemia.Frontiers in immunology · 2026Review
- Identification of a novel diagnostic biomarker for osteoarthritis associated with chromatin regulators based on bioinformatics and experiments.Journal of orthopaedic surgery and research · 2025Article
- Cytokine release syndrome in solid tumors.Cancer · 2025Review
- One step further in targeting acute leukemia by combining antibody-based immunotherapies and small molecule inhibitors.Cancer cell international · 2025Review
- Presetting CAR-T cells during ex vivo biomanufacturing.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- UNC119 regulates T-cell receptor signalling in primary T cells and T acute lymphocytic leukaemia.Life science alliance · 2025Article
- Highly sensitive live-cell imaging-based cytotoxicity assay enables functional validation of rare epitope-specific CTLs.Frontiers in immunology · 2025Article
- Machine Learning and Experimental Validation Reveal MYH11 as a Novel Prognostic Biomarker and Therapeutic Target in Bladder Cancer.Journal of inflammation research · 2025Article
- Approaches for bridging therapy prior to chimeric antigen receptor T cells for relapsed/refractory acute lymphoblastic B-lineage leukemia in children and young adults.Haematologica · 2024Review
- Beyond Conventional Treatments: Exploring CAR-T Cell Therapy for Cancer Stem Cell Eradication.Stem cell reviews and reports · 2024Review
- Bispecific antibodies for multiple myeloma: past, present and future.International journal of hematology · 2024Review
- Dasatinib-induced spleen contraction leads to transient lymphocytosis.Blood advances · 2023Article
- Glycyrrhizin for treatment of CRS caused by CAR T-cell therapy: A pharmacological perspective.Frontiers in pharmacology · 2023Article
- New insights into the Lck-NF-κB signaling pathway.Frontiers in cell and developmental biology · 2023Review
- Src Family Kinases: A Potential Therapeutic Target for Acute Kidney Injury.Biomolecules · 2022Review
Corrections and comments
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Authors and funding
15 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundT cell engagers are bispecific antibodies recognizing, with one moiety, the CD3ε chain of the T cell receptor and, with the other moiety, specific tumor surface antigens. Crosslinking of CD3 upon simultaneous binding to tumor antigens triggers T cell activation, proliferation and cytokine release, leading to tumor cell killing. Treatment with T cell engagers can be associated with safety liabilities due to on-target on-tumor, on-target off-tumor cytotoxic activity and cytokine release syndrome (CRS). Tyrosine kinases such as SRC, LCK or ZAP70 are involved in downstream signaling pathways after engagement of the T cell receptor and blocking these kinases might serve to abrogate T cell activation when required (online supplemental material 1). Dasatinib was previously identified as a potent kinase inhibitor that switches off CAR T cell functionality.
methodsUsing an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of dasatinib combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB, CD19-TCB or HLA-A2 WT1-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. To determine the effective dose of dasatinib, the Incucyte system was used to monitor the kinetics of TCB-mediated target cell killing in the presence of escalating concentrations of dasatinib. Last, the effects of dasatinib were evaluated in vivo in humanized NSG mice co-treated with CD19-TCB. The count of CD20
resultsDasatinib concentrations above 50 nM prevented cytokine release and switched off-target cell killing, which were subsequently restored on removal of dasatinib. In addition, dasatinib prevented CD19-TCB-mediated B cell depletion in humanized NSG mice. These data confirm that dasatinib can act as a rapid and reversible on/off switch for activated T cells at pharmacologically relevant doses as they are applied in patients according to the label.
conclusionTaken together, we provide evidence for the use of dasatinib as a pharmacological on/off switch to mitigate off-tumor toxicities or CRS by T cell bispecific antibodies.
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