期刊
NATURE BIOMEDICAL ENGINEERING
卷 5, 期 5, 页码 399-+出版社
NATURE RESEARCH
DOI: 10.1038/s41551-020-00625-5
关键词
-
资金
- National Institutes of Health [AI69208, CA197605, NS104315]
- Koch Institute Support (core) from the National Cancer Institute [P30-CA14051]
- National Institutes of Health Pre-Doctoral Training Grant [T32GM007287]
- Ivan R. Cottrell Professorship and Research Fund
Therapies using CAR-T cells targeting tumor-specific driver gene mutations show potent and specific cytotoxic activity against acute myeloid leukemia, potentially avoiding harmful effects on normal tissues.
Therapies employing chimeric antigen receptor T cells (CAR-T cells) targeting tumour-associated antigens (TAAs) can lead to on-target-off-tumour toxicity and to resistance, owing to TAA expression in normal tissues and to TAA expression loss in tumour cells. These drawbacks can be circumvented by CAR-T cells targeting tumour-specific driver gene mutations, such as the four-nucleotide duplication in the oncogene nucleophosmin (NPM1c), which creates a neoepitope presented by the human leukocyte antigen with the A2 serotype (HLA-A2) that has been observed in about 35% of patients with acute myeloid leukaemia (AML). Here, we report a human single-chain variable fragment (scFv), identified via yeast surface display, that specifically binds to the NPM1c epitope-HLA-A2 complex but not to HLA-A2 or to HLA-A2 loaded with control peptides. In vitro and in mice, CAR-T cells with the scFv exhibit potent cytotoxicity against NPM1c(+)HLA-A2(+)leukaemia cells and primary AML blasts, but not NPM1c(-)HLA-A2(+)leukaemia cells or HLA-A2(-)tumour cells. Therapies using NPM1c CAR-T cells for the treatment of NPM1c(+)HLA-A2(+)AML may limit on-target-off-tumour toxicity and tumour resistance. CAR-T cells specific for a neoantigen derived from the driver oncogene nucleophosmin display potent and specific cytotoxic activity in mouse models of human acute myeloid leukaemia.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据