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         headline:T cell receptor mimic CAR T cells targeting cathepsin G signal peptide
         description:There has been a been a paucity of immunotherapy targets in myeloid malignancies. We identified the HLA-A2 (A2)-restricted, cathepsin G (CG)-derived signal peptide, CG1, as a promising immunotherapeutic target. CG1 is presented by HLA-A2 in acute (AML) and chronic (CML) myeloid leukemia. We previously developed a T cell receptor-mimic antibody (TCR-m) that targets CG1/A2, engineered it into a bispecific T cell engager antibody, and demonstrated its safety and efficacy in AML and CML. In this study, we provide data for the engineering, preclinical efficacy, and safety of CG1/A2-targeting chimeric antigen receptor (CAR) T cells (CG1/A2-CAR T), which utilize the CG1/A2 TCR-m constructs. We show that the CG1/A2 TCR-m has high affinity for CG1/A2 monomers and CG1/A2-expressing leukemia, including HLA-A2+ AML and CML. We demonstrate potent CG1/A2 CAR T killing of HLA-A2+ AML and CML both in vitro and in vivo. Importantly, we found that CG1/A2-CAR T cells did not affect normal bone marrow hematopoiesis. These results validate signal peptides as immunotherapeutic targets and provide a foundation for the continued clinical development of CG1/A2-CAR T cells in AML and CML.
         datePublished:2025-05-28T00:00:00Z
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      headline:T cell receptor mimic CAR T cells targeting cathepsin G signal peptide
      description:There has been a been a paucity of immunotherapy targets in myeloid malignancies. We identified the HLA-A2 (A2)-restricted, cathepsin G (CG)-derived signal peptide, CG1, as a promising immunotherapeutic target. CG1 is presented by HLA-A2 in acute (AML) and chronic (CML) myeloid leukemia. We previously developed a T cell receptor-mimic antibody (TCR-m) that targets CG1/A2, engineered it into a bispecific T cell engager antibody, and demonstrated its safety and efficacy in AML and CML. In this study, we provide data for the engineering, preclinical efficacy, and safety of CG1/A2-targeting chimeric antigen receptor (CAR) T cells (CG1/A2-CAR T), which utilize the CG1/A2 TCR-m constructs. We show that the CG1/A2 TCR-m has high affinity for CG1/A2 monomers and CG1/A2-expressing leukemia, including HLA-A2+ AML and CML. We demonstrate potent CG1/A2 CAR T killing of HLA-A2+ AML and CML both in vitro and in vivo. Importantly, we found that CG1/A2-CAR T cells did not affect normal bone marrow hematopoiesis. These results validate signal peptides as immunotherapeutic targets and provide a foundation for the continued clinical development of CG1/A2-CAR T cells in AML and CML.
      datePublished:2025-05-28T00:00:00Z
      dateModified:2025-05-28T00:00:00Z
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         Cancer immunotherapy
         Immunotherapy
         Preclinical research
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         Intensive / Critical Care Medicine
         Cancer Research
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         Hematology
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