Persistent URL of this record https://hdl.handle.net/1887/3250573
Documents
-
- Download
- 122281495_publishedVersion_None
- Publisher's Version
-
open access
- Full text at publishers site
In Collections
This item can be found in the following collections:
An HLA-A*11:01-binding neoantigen from mutated NPM1 as target for TCR gene therapy in AML
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.Show less
- All authors
- Lee, D.I. van der; Koutsoumpli, G.; Reijmers, R.M.; Honders, M.W.; Jong, R.C.M. de; Remst, D.F.G.; Wachsmann, T.L.A.; Hagedoorn, R.S.; Franken, K.L.M.C.; Kester, M.G.D.; Harber, K.J.; Roelofsen, L.M.; Schouten, A.M.; Mulder, A.; Drijfhout, J.W.; Veelken, H.; Veelen, P.A. van; Heemskerk, M.H.M.; Falkenburg, J.H.F.; Griffioen, M.
- Date
- 2021-11-01
- Journal
- Cancers
- Volume
- 13
- Issue
- 21