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 n...

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Autores principales:	Dyantha I. van der Lee, Georgia Koutsoumpli, Rogier M. Reijmers, Willy Honders, Rob C. M. de Jong, Dennis F. G. Remst, Tassilo L. A. Wachsmann, Renate S. Hagedoorn, Kees L. M. C. Franken, Michel G. D. Kester, Karl J. Harber, Lisanne M. Roelofsen, Annemiek M. Schouten, Arend Mulder, Jan W. Drijfhout, Hendrik Veelken, Peter A. van Veelen, Mirjam H. M. Heemskerk, Frederik Falkenburg, Marieke Griffioen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	acute myeloid leukemia neoantigens cancer immunotherapy T-cell receptor gene therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/c17f00de15f74c7e976015e4595c0f2e
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spelling	oai:doaj.org-article:c17f00de15f74c7e976015e4595c0f2e2021-11-11T15:29:50ZAn HLA-A11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML10.3390/cancers132153902072-6694https://doaj.org/article/c17f00de15f74c7e976015e4595c0f2e2021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5390https://doaj.org/toc/2072-6694Acute 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-A02:01-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-A11:01. The TCR cloned from a T-cell clone recognizing HLA-A11:01+ 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-A11:01+ primary AMLs. CD8 cells transduced with an HLA-A11:01-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.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 W. DrijfhoutHendrik VeelkenPeter A. van VeelenMirjam H. M. HeemskerkFrederik FalkenburgMarieke GriffioenMDPI AGarticleacute myeloid leukemianeoantigenscancer immunotherapyT-cell receptor gene therapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5390, p 5390 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	acute myeloid leukemia neoantigens cancer immunotherapy T-cell receptor gene therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	acute myeloid leukemia neoantigens cancer immunotherapy T-cell receptor gene therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Dyantha I. van der Lee Georgia Koutsoumpli Rogier M. Reijmers Willy Honders Rob C. M. de Jong Dennis F. G. Remst Tassilo L. A. Wachsmann Renate S. Hagedoorn Kees L. M. C. Franken Michel G. D. Kester Karl J. Harber Lisanne M. Roelofsen Annemiek M. Schouten Arend Mulder Jan W. Drijfhout Hendrik Veelken Peter A. van Veelen Mirjam H. M. Heemskerk Frederik Falkenburg Marieke Griffioen An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML
description	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-A02:01-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-A11:01. The TCR cloned from a T-cell clone recognizing HLA-A11:01+ 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-A11:01+ 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.
format	article
author	Dyantha I. van der Lee Georgia Koutsoumpli Rogier M. Reijmers Willy Honders Rob C. M. de Jong Dennis F. G. Remst Tassilo L. A. Wachsmann Renate S. Hagedoorn Kees L. M. C. Franken Michel G. D. Kester Karl J. Harber Lisanne M. Roelofsen Annemiek M. Schouten Arend Mulder Jan W. Drijfhout Hendrik Veelken Peter A. van Veelen Mirjam H. M. Heemskerk Frederik Falkenburg Marieke Griffioen
author_facet	Dyantha I. van der Lee Georgia Koutsoumpli Rogier M. Reijmers Willy Honders Rob C. M. de Jong Dennis F. G. Remst Tassilo L. A. Wachsmann Renate S. Hagedoorn Kees L. M. C. Franken Michel G. D. Kester Karl J. Harber Lisanne M. Roelofsen Annemiek M. Schouten Arend Mulder Jan W. Drijfhout Hendrik Veelken Peter A. van Veelen Mirjam H. M. Heemskerk Frederik Falkenburg Marieke Griffioen
author_sort	Dyantha I. van der Lee
title	An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML
title_short	An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML
title_full	An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML
title_fullStr	An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML
title_full_unstemmed	An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML
title_sort	hla-a*11:01-binding neoantigen from mutated npm1 as target for tcr gene therapy in aml
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c17f00de15f74c7e976015e4595c0f2e
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An HLA-A*11:01-Binding Neoantigen from Mutated NPM1 as Target for TCR Gene Therapy in AML

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