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PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer

Recurrent disease emerges in the majority of patients with ovarian cancer (OVCA). Adoptive T-cell therapies with T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) are considered promising solutions for less-immunogenic ‘cold’ ovarian tumors. In order to treat a broader patient popul...

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Autores principales: van Amerongen, Rosa A., Tuit, Sander, Wouters, Anne K., van de Meent, Marian, Siekman, Sterre L., Meeuwsen, Miranda H., Wachsmann, Tassilo L. A., Remst, Dennis F. G., Hagedoorn, Renate S., van der Steen, Dirk M., de Ru, Arnoud H., Verdegaal, Els M. E., van Veelen, Peter A., Falkenburg, J. H. Frederik, Heemskerk, Mirjam H. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070997/
https://www.ncbi.nlm.nih.gov/pubmed/37026005
http://dx.doi.org/10.3389/fimmu.2023.1121973
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author van Amerongen, Rosa A.
Tuit, Sander
Wouters, Anne K.
van de Meent, Marian
Siekman, Sterre L.
Meeuwsen, Miranda H.
Wachsmann, Tassilo L. A.
Remst, Dennis F. G.
Hagedoorn, Renate S.
van der Steen, Dirk M.
de Ru, Arnoud H.
Verdegaal, Els M. E.
van Veelen, Peter A.
Falkenburg, J. H. Frederik
Heemskerk, Mirjam H. M.
author_facet van Amerongen, Rosa A.
Tuit, Sander
Wouters, Anne K.
van de Meent, Marian
Siekman, Sterre L.
Meeuwsen, Miranda H.
Wachsmann, Tassilo L. A.
Remst, Dennis F. G.
Hagedoorn, Renate S.
van der Steen, Dirk M.
de Ru, Arnoud H.
Verdegaal, Els M. E.
van Veelen, Peter A.
Falkenburg, J. H. Frederik
Heemskerk, Mirjam H. M.
author_sort van Amerongen, Rosa A.
collection PubMed
description Recurrent disease emerges in the majority of patients with ovarian cancer (OVCA). Adoptive T-cell therapies with T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) are considered promising solutions for less-immunogenic ‘cold’ ovarian tumors. In order to treat a broader patient population, more TCRs targeting peptides derived from different TAAs binding in various HLA class I molecules are essential. By performing a differential gene expression analysis using mRNA-seq datasets, PRAME, CTCFL and CLDN6 were selected as strictly tumor-specific TAAs, with high expression in ovarian cancer and at least 20-fold lower expression in all healthy tissues of risk. In primary OVCA patient samples and cell lines we confirmed expression and identified naturally expressed TAA-derived peptides in the HLA class I ligandome. Subsequently, high-avidity T-cell clones recognizing these peptides were isolated from the allo-HLA T-cell repertoire of healthy individuals. Three PRAME TCRs and one CTCFL TCR of the most promising T-cell clones were sequenced, and transferred to CD8+ T cells. The PRAME TCR-T cells demonstrated potent and specific antitumor reactivity in vitro and in vivo. The CTCFL TCR-T cells efficiently recognized primary patient-derived OVCA cells, and OVCA cell lines treated with demethylating agent 5-aza-2′-deoxycytidine (DAC). The identified PRAME and CTCFL TCRs are promising candidates for the treatment of patients with ovarian cancer, and are an essential addition to the currently used HLA-A*02:01 restricted PRAME TCRs. Our selection of differentially expressed genes, naturally expressed TAA peptides and potent TCRs can improve and broaden the use of T-cell therapies for patients with ovarian cancer or other PRAME or CTCFL expressing cancers.
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spelling pubmed-100709972023-04-05 PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer van Amerongen, Rosa A. Tuit, Sander Wouters, Anne K. van de Meent, Marian Siekman, Sterre L. Meeuwsen, Miranda H. Wachsmann, Tassilo L. A. Remst, Dennis F. G. Hagedoorn, Renate S. van der Steen, Dirk M. de Ru, Arnoud H. Verdegaal, Els M. E. van Veelen, Peter A. Falkenburg, J. H. Frederik Heemskerk, Mirjam H. M. Front Immunol Immunology Recurrent disease emerges in the majority of patients with ovarian cancer (OVCA). Adoptive T-cell therapies with T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) are considered promising solutions for less-immunogenic ‘cold’ ovarian tumors. In order to treat a broader patient population, more TCRs targeting peptides derived from different TAAs binding in various HLA class I molecules are essential. By performing a differential gene expression analysis using mRNA-seq datasets, PRAME, CTCFL and CLDN6 were selected as strictly tumor-specific TAAs, with high expression in ovarian cancer and at least 20-fold lower expression in all healthy tissues of risk. In primary OVCA patient samples and cell lines we confirmed expression and identified naturally expressed TAA-derived peptides in the HLA class I ligandome. Subsequently, high-avidity T-cell clones recognizing these peptides were isolated from the allo-HLA T-cell repertoire of healthy individuals. Three PRAME TCRs and one CTCFL TCR of the most promising T-cell clones were sequenced, and transferred to CD8+ T cells. The PRAME TCR-T cells demonstrated potent and specific antitumor reactivity in vitro and in vivo. The CTCFL TCR-T cells efficiently recognized primary patient-derived OVCA cells, and OVCA cell lines treated with demethylating agent 5-aza-2′-deoxycytidine (DAC). The identified PRAME and CTCFL TCRs are promising candidates for the treatment of patients with ovarian cancer, and are an essential addition to the currently used HLA-A*02:01 restricted PRAME TCRs. Our selection of differentially expressed genes, naturally expressed TAA peptides and potent TCRs can improve and broaden the use of T-cell therapies for patients with ovarian cancer or other PRAME or CTCFL expressing cancers. Frontiers Media S.A. 2023-03-21 /pmc/articles/PMC10070997/ /pubmed/37026005 http://dx.doi.org/10.3389/fimmu.2023.1121973 Text en Copyright © 2023 van Amerongen, Tuit, Wouters, van de Meent, Siekman, Meeuwsen, Wachsmann, Remst, Hagedoorn, van der Steen, de Ru, Verdegaal, van Veelen, Falkenburg and Heemskerk https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
van Amerongen, Rosa A.
Tuit, Sander
Wouters, Anne K.
van de Meent, Marian
Siekman, Sterre L.
Meeuwsen, Miranda H.
Wachsmann, Tassilo L. A.
Remst, Dennis F. G.
Hagedoorn, Renate S.
van der Steen, Dirk M.
de Ru, Arnoud H.
Verdegaal, Els M. E.
van Veelen, Peter A.
Falkenburg, J. H. Frederik
Heemskerk, Mirjam H. M.
PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer
title PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer
title_full PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer
title_fullStr PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer
title_full_unstemmed PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer
title_short PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer
title_sort prame and ctcfl-reactive tcrs for the treatment of ovarian cancer
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10070997/
https://www.ncbi.nlm.nih.gov/pubmed/37026005
http://dx.doi.org/10.3389/fimmu.2023.1121973
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