T cells dressed up with a dual HLA-restricted TCR targeting Cathepsin G drive effective leukemia eradication

ABSTRACT: Despite immunosensitivity, genetic heterogeneity, low mutational burden and lack of tumor-specific antigens hinder immunotherapy success for acute myeloid leukemia (AML). T cell receptors (TCRs) offer a promising route by targeting tumor-relevant intracellular antigens shared across AML subtypes; however human leukocyte antigen (HLA) restriction limits their potential. We identified a potent TCR capable of recognizing peptides of Cathepsin G (CTSG), a serine protease confined to neutrophil granules but aberrantly localized in the cytoplasm of leukemic blasts, when presented by HLA-A*24:02 and HLA-C*07:02, highly frequent alleles. Leveraging TCR gene-editing and CD8 co-receptor transduction, we engineered a robust T cell army, comprising cytotoxic CD8+ and CD4+CD8+ T lymphocytes with enhanced helper activity. Noticeably, CTSG-TCR T cells exhibited potent and specific cytotoxicity against primary AML blasts, culminating in complete in vivo disease eradication and a favorable safety profile. These results reveal the potential of dual restricted TCRs, and of CTSG-TCR T cells as powerful therapeutics for a broad AML patient population

ORGANISM(S): Homo sapiens

PROVIDER: GSE298290 | GEO | 2026/10/06

REPOSITORIES: GEO