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

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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 (T EM ) expressing higher levels of cytotoxic genes and their transcriptional regulator ZNF683 . Conversely, CD8 + T EM 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 + T EM . 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 + T EM and an immunosuppressive milieu. This provides a rationale for risk stratification based on baseline transcriptional profiling of CD8 + T EM and for combinatorial strategies targeting the suppressive microenvironment.

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