An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML.
Dyantha I van der LeeGeorgia KoutsoumpliRogier M ReijmersWilly HondersRob C M de JongDennis F G RemstTassilo L A WachsmannRenate S HagedoornKees L M C FrankenMichel G D KesterKarl J HarberLisanne M RoelofsenAnnemiek M SchoutenArend MulderJan Wouter DrijfhoutHendrik VeelkenPeter A van VeelenMirjam H M HeemskerkFrederik FalkenburgMarieke GriffioenPublished in: Cancers (2021)
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.
Keyphrases
- acute myeloid leukemia
- induced apoptosis
- allogeneic hematopoietic stem cell transplantation
- cell cycle arrest
- poor prognosis
- regulatory t cells
- mouse model
- oxidative stress
- type diabetes
- endothelial cells
- gene therapy
- cell proliferation
- genome wide
- bone marrow
- skeletal muscle
- metabolic syndrome
- adipose tissue
- radiation therapy
- climate change
- binding protein
- mesenchymal stem cells
- nk cells