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Rohrbacher, L.* ; Nixdorf, D.* ; Stadler, H.* ; Brauchle, B.* ; Märkl, F.* ; Gottschlich, A.* ; Hoffmann, G.V.* ; Philipp, N.* ; Hänel, G.* ; Kirmaier, M.E.* ; Marcinek, A.* ; Kazerani, M.* ; Richter, D.* ; Magno, G.* ; Goldstein, R.L.* ; Theurich, S.* ; Straub, T.* ; Kobold, S. ; Arvedson, T.* ; Bücklein, V.* ; Subklewe, M.*

FLT3-directed BiTE molecules vs CAR T cells in AML: Costimulatory signals mitigate T-cell exhaustion.

Blood Adv. 10, 1179-1193 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
T-cell–based immunotherapies have revolutionized treatment paradigms in B-cell malignancies, yet their translation to acute myeloid leukemia (AML) has been hindered by a scarcity of tumor-restricted antigens and the risk of on-target off-leukemia toxicity. FLT3 has emerged as a promising therapeutic target with limited expression in healthy hematopoietic tissues. Here, we performed a head-to-head preclinical comparison of an FMS-like tyrosine kinase 3 (FLT3)-directed bispecific T-cell engager (BiTE) molecule and second-generation FLT3-specific chimeric antigen receptor (CAR) T cells. Both approaches induced potent cytotoxicity against AML cell lines and primary patient-derived cells but spared healthy hematopoietic stem and progenitor cells in vitro. Despite similar short-term efficacy, prolonged antigen exposure demonstrated progressive functional decline and metabolic exhaustion; however, CAR T cells maintained cytotoxic capacity and proliferative potential over time. In AML xenograft models, CAR T cells achieved superior tumor control, prolonged survival, and greater T-cell infiltration than BiTE molecule–treated counterparts. Transcriptomic profiling of T cells recovered from the bone marrow further revealed a distinct exhaustion-associated gene signature in samples from mice that had been treated with the FLT3 BiTE molecule. Importantly, provision of CD86-mediated costimulation enhanced antitumor activity of BiTE-redirected T cells in vitro and in vivo. These findings establish FLT3 as a viable and selective immunotherapeutic target in AML and underscore the functional and transcriptional differences between BiTE molecule–redirected T cells and CAR T cells. Moreover, they reveal a critical role for costimulatory signaling in sustaining the efficacy of T-cell–based therapies in vivo, offering a rationale for improving T cell–redirection strategies in myeloid malignancies.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Myeloid-leukemia; Tyrosine Kinase; Flt3 Ligand; Receptor; Chemotherapy; Expression; Therapy; Surface; Target; Cd33
ISSN (print) / ISBN 2473-9529
e-ISSN 2473-9537
Journal Blood advances
Quellenangaben Volume: 10, Issue: 4, Pages: 1179-1193 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place Washington, DC
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)