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. 2025 Aug 12;9(15):3689-3693.
doi: 10.1182/bloodadvances.2025015894.

T-cell dysfunction during blinatumomab therapy in pediatric acute lymphoblastic leukemia

Julie Ma  1 , Annie Luong  2 , Andrew Doan  1   3 , Tsen Yin Lin  2 , Lingyun Ji  4 , Cassandra P Wang  1 , Seon-Jae Yoon  1 , Teresa Rushing  1   5 , Anh Duong  2 , Miguel Villa  1 , Chintan Parekh  1   3
Affiliations

T-cell dysfunction during blinatumomab therapy in pediatric acute lymphoblastic leukemia

Julie Ma et al. Blood Adv. .
No abstract available

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Conflict of interest statement

Conflict-of-interest disclosure: C.P. reports equity holding in a private company, Pluto Immunotherapeutics, Inc; receiving royalties for technology licensed to Pluto that are unrelated to this study; and spouse being a former employee of Amgen and owning Amgen stock. The remaining authors declare no competing financial interests.

The current affiliation for J.M. is Pediatric Oncology Branch, Cancer for Center Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

The current affiliation for A.L., S.-J.Y., M.V., and C.P. is Department of Pediatrics, City of Hope Comprehensive Cancer Center, Duarte, CA.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
T cells show functional, phenotypic, and transcriptional evidence of dysfunction during continuous blinatumomab. T cells collected at baseline (preblinatumomab), middle (day 14), and end time points (day 28) during a 28-day continuous blinatumomab infusion were analyzed. (A) Left plot: cytotoxicity of T cells. Line graph (right): time point-matched data; each line represents a patient. Green diamonds, cytotoxicity sustained; purple triangles, cytotoxicity not sustained. Vertical bracket: Mann-Whitney test comparison of baseline data. (B-E) Frequency of TSCM, TEMRA, TIM3+, IFN-γ+, TNF-α+, p-mTOR+, p-MEK+, and p-S6+ cells among all T cells. p-S6: marker of mTOR activity. (D-E) Data from intracellular flow cytometry analysis after coculture of T cells and B-ALL cells with CD19/CD3 BiTE antibody. Values relative to control cocultures (positive cells [%]with BiTE − positive [%]without BiTE) are shown. (F) Volcano plot of fold change vs statistical significance from DESeq differential gene expression analysis (day 14 vs day 0). Differentially expressed genes (FDR adjusted P < .15) in dark red. AFF3, a cofactor highly expressed in progenitors of exhausted T cells; LAYN, MAGEH1, genes related to T-regulatory suppressive function; LYST, lysosomal trafficking gene associated with T-cell dysfunction. Dotted vertical line: −log10 P value cutoff for defining differential expression. (G) Gene set enrichment analysis for T-cell exhaustion (acute lymphocytic choriomeningitis virus [LCMV] vs chronic [exhausted T cells] LCMV), TEMRA (naive T cells vs PD1 low [enriched for TEMRA] T cells), terminally differentiated effector (KLRG1 high [terminal effector] vs KLRG low12), and effector gene sets among genes ranked by day 14 vs day 0 expression. (A-E) Box plots: 25th to 75th percentiles. Whiskers: 1.5 × the interquartile range beyond 25th and 75th percentiles. Thick black horizontal line, median; red triangle, mean; blue circles, individual data points. P value (blue): Friedman test (TSCM, TIM3+, IFN-γ+, and TNF-α+) or 1-way repeated-measures analysis of variance (all others). Horizontal line (red): paired t test or Wilcox test (Holm-Sidak correction for multiple comparisons). ∗P < .05; ∗∗P < .01. N = 10 patients for panels A, D, and E and 11 patients for panels B, C, F, and G. DN, down; FDR, false discovery rate; GS, gene set; IFN-γ, interferon gamma; KLRG, killer cell lectin-like receptor subfamily G member; mTOR, mammalian target of rapamycin; NES, normalized enrichment score; PD1, programmed cell death protein 1; Tfh, T follicular helper; Th1, type 1 helper T cell; TNF-α, tumor necrosis factor alpha.
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