An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML.

Autor: van der Lee DI; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Koutsoumpli G; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Reijmers RM; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Honders MW; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., de Jong RCM; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Remst DFG; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Wachsmann TLA; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Hagedoorn RS; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Franken KLMC; Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Kester MGD; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Harber KJ; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Roelofsen LM; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Schouten AM; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Mulder A; Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Drijfhout JW; Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Veelken H; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., van Veelen PA; Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Heemskerk MHM; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Falkenburg JHF; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Griffioen M; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2021 Oct 27; Vol. 13 (21). Date of Electronic Publication: 2021 Oct 27.
DOI: 10.3390/cancers13215390
Abstrakt: Acute myeloid leukemia (AML) is a hematological malignancy caused by clonal expansion of myeloid progenitor cells. Most patients with AML respond to chemotherapy, but relapses often occur and infer a very poor prognosis. Thirty to thirty-five percent of AMLs carry a four base pair insertion in the nucleophosmin 1 gene (NPM1) with a C-terminal alternative reading frame of 11 amino acids. We previously identified various neopeptides from the alternative reading frame of mutant NPM1 (dNPM1) on primary AML and isolated an HLA-A*02:01-restricted T-cell receptor (TCR) that enables human T-cells to kill AML cells upon retroviral gene transfer. Here, we isolated T-cells recognizing the dNPM1 peptide AVEEVSLRK presented in HLA-A*11:01. The TCR cloned from a T-cell clone recognizing HLA-A*11:01+ primary AML cells conferred in vitro recognition and lysis of AML upon transfer to CD8 cells, but failed to induce an anti-tumor effect in immunodeficient NSG mice engrafted with dNPM1 OCI-AML3 cells. In conclusion, our data show that AVEEVSLRK is a dNPM1 neoantigen on HLA-A*11:01+ primary AMLs. CD8 cells transduced with an HLA-A*11:01-restricted TCR for dNPM1 were reactive against AML in vitro. The absence of reactivity in a preclinical mouse model requires further preclinical testing to predict the potential efficacy of this TCR in clinical development.
Databáze: MEDLINE
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