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CD4+/CD8+ selection of anti-AML engager T cells alters their manufacturing environment, transcriptome, and functional phenotype

ABSTRACT: Immunotherapies have shown efficacy against some cancers. Despite initial clearance, relapse rates are high, demanding product improvement. A variety of manufacturing methods protocols are used to generate therapeutic engineered T-cells; these differ in T-cell isolation, activation, and genetic modification, and other methodology. We sought to determine how manufacturing differencespre-selection affected the phenotype of T cells engineered to secrete a CD123xCD3 bispecific engager molecule (ENG-T). These cells were designed to treat acute myeloid leukemia (AML). We evaluated the effect of T-cell selection on transduction efficiency, T-cell activation, short- and long-term anti-AML cytotoxicity, and gene transcription. Unselected, CD4, CD8, and CD4/CD8-selected ENG-T cells had minor differences in immunophenotype but demonstrated equivalent activation and cytotoxicity in short-term assays. While unselected and CD4/CD8-selected ENG-T cells appeared similar phenotypically prior to target cell exposure, serial stimulation in vitro showed CD4/CD8-selection supported sustained ENG-T survival. Likewise, CD4 and CD4/CD8-selected ENG-T cells displayed superior anti-tumor efficacy and murine survival in AML xenografts. Unselected ENG-T cells were found to be exposed to inflammatory cytokines during early manufacture with transcriptional analysis revealing upregulation of intracellular inflammatory pathways. This early activation likely underpins long-term observed functional differences. Pre-selection of T-cell products should therefore be strongly considered to enhance the quality of clinical cell therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277096 | GEO | 2025/09/12

REPOSITORIES: GEO

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CD4+/CD8+ selection of anti-AML engager T cells alters their manufacturing environment, transcriptome, and functional phenotype

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