Open AccessCAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia
Author(s) -
Guozhu Xie,
Nikola A. Ivica,
Bin Jia,
Yingzhong Li,
Dong Han,
Yong Liang,
Deborah A. Brown,
Rizwan Romee,
Jianzhu Chen
Publication year - 2020
Publication title -
nature biomedical engineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.961
H-Index - 56
ISSN - 2157-846X
DOI - 10.1038/s41551-020-00625-5
Subject(s) - antigen , cancer research , myeloid , biology , human leukocyte antigen , epitope , cytotoxic t cell , immunology , in vitro , genetics
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.