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Corrado, F.* ; Blumenberg, V.* ; Kazerani, M.* ; Wulf, J.* ; Straub, T.* ; Philipp, N.* ; Nixdorf, D.* ; Muth, A.* ; Rappa, G.* ; Petrera, A. ; Scheurer, M.* ; Chu, C.F.* ; Magno, G.* ; Zielinski, C.E.* ; von Bergwelt-Baildon, M.* ; Subklewe, M.* ; Bücklein, V.*

Pre-treatment T cell features and immune-milieu characteristics shape treatment-induced exhaustion and resistance to Blinatumomab in B-cell acute lymphoblastic leukemia.

Front. Immunol. 17:1895742 (2026)
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Background: Blinatumomab (Blina), a CD19×CD3 bispecific T cell engager, is approved for the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), yet resistance remains a major challenge and the mechanisms driving treatment failure remain poorly understood. Methods: To define the immunological determinants of resistance, we performed longitudinal profiling of peripheral blood T cells and the immune milieu of 34 patients receiving Blina using flow cytometry (n=19), single-cell CITE-seq (n=13), ex vivo Blina-induced cytotoxicity (n=26) and serum proteomics (n=17). Results: At baseline, Responders (R) were enriched for CD8+ effector memory T cells (TEM) expressing higher levels of cytotoxic genes and their transcriptional regulator ZNF683. Conversely, CD8+ TEM from Non-Responders (NR) displayed transcriptional features of activation without proportionate cytotoxic commitment. Over the course of the first treatment cycle, NR exhibited a progressive expansion of TIM3+CD8+ T cells that correlated with a rapid loss of ex vivo cytotoxic function. Linking baseline state to post-treatment T-cell exhaustion, the magnitude of TIM3+CD8+ expansion correlated inversely with baseline ZNF683 expression in CD8+TEM. Beyond T-cell-intrinsic features, NR harbored an immunosuppressive milieu characterized by higher circulating levels of M2-polarizing factors (CSF-1, HGF) and the TIM-3 ligand Galectin-9, which correlated positively with the magnitude of TIM3+CD8+ T-cell expansion. Conclusions: These findings indicate that post-Blina CD8+ T-cell exhaustion is associated with resistance and it is shaped by both reduced ZNF683-dependent cytotoxic programming in CD8+ TEM and an immunosuppressive milieu. This provides a rationale for risk stratification based on baseline transcriptional profiling of CD8+ TEM and for combinatorial strategies targeting the suppressive microenvironment.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute B Cell Lymphoblastic Leukemia ; Multiomic Analyses ; Proteomic Analysis ; Single Cell Cite Sequencing ; T Cell Redirecting Bispecific Antibodies (bsabs)
ISSN (print) / ISBN 1664-3224
e-ISSN 1664-3224
Journal Frontiers in Immunology
Quellenangaben Volume: 17, Issue: , Pages: , Article Number: 1895742 Supplement: ,
Publisher Frontiers
Publishing Place Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
Reviewing status Peer reviewed
Institute(s) Core Facility Metabolomics and Proteomics (CF-MPC)
Grants Deutsche Forschungsgemeinschaft (DFG)