Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 10, Pages 5127-5141Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI137723
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Funding
- Bill and Melinda Gates Foundation
- Hyundai Hope on Wheels [TE 6705]
- Stand Up To Cancer Innovative Research Grant [SU2C-AACR-IRG 14-17]
- American Association for Cancer Research, the scientific partner of SU2C
- National Cancer Institute Paul Calabresi Career Development Award for Clinical Oncology [5 K12 CA076930-18]
- Rally Foundation for Childhood Cancer Research
- Alex's Lemonade Stand-Foundation for Childhood Cancer
- Fred Hutch Immunotherapy Integrated Research Center
- Shared Resources (Comparative Medicine, Flow Cytometry, and Experimental Histopathology) of the Fred Hutch/University of Washington Cancer Consortium [P30 CA015704]
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Proteins created from recurrent fusion genes like CBFB-MYH11 are prevalent in acute myeloid leukemia (AML), often necessary for leukemogenesis, persistent throughout the disease course, and highly leukemia specific, making them attractive neoantigen targets for immunotherapy. A nonameric peptide derived from a prevalent CBFB-MYH11 fusion protein was found to be immunogenic in HLA-B*40:01* donors. High-avidity CD8(+) T cell clones isolated from healthy donors killed CBFB-MYHir HLA-B*40:01(+) AML cell lines and primary human AML samples in vitro. CBFB-MYH11-specific T cells also controlled CBFB-MYH11(+) HLA-B*40:01(+) AML in vivo in a patient-derived murine xenograft model. High-avidity CBFBM-YH11 epitope-specific T cell receptors (TCRs) transduced into CO8 . T cells conferred antileukemic activity in vitro. Our data indicate that the CBFB-MYH11 fusion neoantigen is naturally presented on AML blasts and enables T cell recognition and killing of AML. We provide proof of principle for immunologically targeting AML-initiating fusions and demonstrate that targeting neoantigens has clinical relevance even in low-mutational frequency cancers like fusion-driven AML. This work also represents a first critical step toward the development of TCR T cell immunotherapy targeting fusion gene-driven AML.
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