Using yeast surface display, Xie et al. identified a human scFv that binds specifically and with high affinity to HLA-A*0201 complexed with AIQ, a leukemia-specific neoepitope derived from the mutant nucleophosmin oncoprotein (NPM1c) common in patients with acute myeloid leukaemia (AML). Human CD8+ T cells transduced with 4-1BB-CD3ζ-CARs comprising the scFv specifically killed NPM1c+ HLA-A2+ tumor lines and primary human AML blasts in vitro, and in mouse models, controlled NPM1c+ HLA-A2+ leukemia cell line burden in liver, blood, spleen, and bone marrow to prolong host survival, and killed patient-derived AML blast xenografts.
Contributed by Paula Hochman
ABSTRACT: 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.
Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambrid
Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. (2) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. (3) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. (4) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. (5) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA. (6) Division of Hematologic Malignancies and Transplantation, Dana-Farber Cancer Institute, Boston, MA, USA. (7) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. (8) Division of Hematologic Malignancies and Transplantation, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. jchen@mit.edu. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. jchen@mit.edu.
