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A T-cell receptor targeting RUNX1 frameshift mutations in acute myeloid leukemia

ABSTRACT: Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoietic differentiation. Disruption of RUNX1 in acute myeloid leukemia (AML) induces a maturation arrest and early myeloid progenitor phenotype. RUNX1 mutations occur in 10-15% of AML and are associated with poor prognosis. One-third are frameshift mutations encoding an oncogenic protein with an elongated C-terminus translated in an alternative reading frame. Here, we investigated whether the alternative reading frame of oncogenic RUNX1 can be targeted by immunotherapy. We introduced a construct with a RUNX1 frameshift mutation into EBV-B cells with common HLA class I alleles and identified 13 neopeptides by HLA-immunopeptidomics. To investigate whether these peptides are neoantigens that can be recognized by T cells, peptide-MHC tetramers were used to screen 42 healthy individuals for specific CD8 T cells. T-cell clones were isolated for 6 neopeptides in 5 HLA alleles. Three T-cell clones recognized two HLA-B*07:02 neoantigens on AML cell line SIG-M5 C9, which was edited by CRISPR/Cas9 to express a RUNX1 frameshift mutation. The T-cell receptors (TCRs) of these clones were sequenced, and analyzed after transfer to CD8 T cells. One TCR showed effective killing of SIG-M5 C9 in vitro and in immunodeficient mice. The TCR-engineered T cells also killed patient-derived AML cells with early progenitor phenotypes, including leukemic stem cells. In conclusion, we showed that the alternative reading frame created by RUNX1 frameshift mutations can be effectively targeted, demonstrating the potential relevance of TCR-based immunotherapy to treat and improve the prognosis of patients with RUNX1-mutated AML.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Blood Cell, T Cell, Cell Culture, Bone Marrow, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Rayman Tjokrodirijo

LAB HEAD: Peter A. van Veelen

PROVIDER: PXD062938 | Pride | 2025-07-31

REPOSITORIES: pride

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Project description:Background Clinical success of T cell receptor (TCR) gene therapy has previously been demonstrated for NY-ESO-1 TCR gene therapy. To increase numbers of cancer patients that can be treated with TCR gene therapy we aimed to identify a novel set of high-affinity cancer specific TCRs targeting different cancer testis (CT) antigens in prevalent HLA class I alleles. Methods In this study, we selected based on publicly available gene expression databases the most promising CT genes to target. From these selected genes we identified by HLA peptidomics the naturally processed and presented HLA class I peptides. With these peptide-HLA tetramers were generated, and by single cell sorting CT specific CD8+ T cells were selected, and expanded from the allo-HLA repertoire of healthy donors. By several functional assays high avidity CT-specific T cell clones with safe recognition pattern were selected. To evaluate the potential for clinical application in TCR gene therapy, TCRs were sequenced and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 in the context of human leukocyte antigen(HLA) -A1, -A2, -A3, -B7, -B35 and -C7. TCR gene transfer into CD8⁺ T cells resulted in efficient cytokine production and cytotoxicity of variety of different tumor types without detectable cross-reactivity. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells was observed in an orthotopic xenograft model for established multiple myeloma, in which bone marrow located tumor cells were completely eradicated after T cell injection. Conclusion The identification of 7 novel CT-specific TCRs, reactive against CT antigens presented in a variety of different HLA class I alleles, allows selection of therapeutic TCRs for an increased number of cancer patients, and will improve development of personalized TCR gene therapy.

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A T-cell receptor targeting RUNX1 frameshift mutations in acute myeloid leukemia

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