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- Title
An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML.
- Authors
van der Lee, Dyantha I.; Koutsoumpli, Georgia; Reijmers, Rogier M.; Honders, Willy; de Jong, Rob C. M.; Remst, Dennis F. G.; Wachsmann, Tassilo L. A.; Hagedoorn, Renate S.; Franken, Kees L. M. C.; Kester, Michel G. D.; Harber, Karl J.; Roelofsen, Lisanne M.; Schouten, Annemiek M.; Mulder, Arend; Drijfhout, Jan W.; Veelken, Hendrik; van Veelen, Peter A.; Heemskerk, Mirjam H. M.; Falkenburg, Frederik; Griffioen, Marieke
- Abstract
Simple Summary: Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis. For AML relapses after chemotherapy, new and effective therapies are needed. In 30–35% of AMLs, a frameshift mutation in the nucleophosmin 1 gene (dNPM1) creates potential neoantigens that are attractive targets for immunotherapy. We previously isolated a T-cell receptor (TCR) that targets an HLA-A*02:01-binding dNPM1 neoantigen on primary AML. Here, we investigated whether AVEEVSLRK is another dNPM1 neoantigen that can be targeted by TCR gene transfer. We isolated various T-cells, cloned the HLA-A*11:01-restricted TCR from one T-cell clone and, upon transfer to CD8 cells, demonstrated targeting of dNPM1 primary AMLs in vitro. However, the TCR failed to mediate an anti-tumor effect in immunodeficient mice engrafted with dNPM1 OCI-AML3 cells. Our results demonstrate that AVEEVSLRK is an HLA-A*11:01-binding neoantigen on dNPM1 AML. Whether the isolated TCR is of sufficient affinity to treat patients remains uncertain. 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.
- Subjects
AMINO acid metabolism; ACUTE myeloid leukemia treatment; IN vitro studies; HLA-B27 antigen; GENETIC mutation; ANIMAL experimentation; CELL receptors; GENE therapy; TUMOR antigens; IMMUNOTHERAPY; MICE
- Publication
Cancers, 2021, Vol 13, Issue 21, p5390
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers13215390