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Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma

5T4 (trophoblast glycoprotein, TPBG) is a transmembrane tumor antigen expressed on more than 90% of primary renal cell carcinomas (RCC) and a wide range of human carcinomas but not on most somatic adult tissues. The favorable expression pattern has encouraged the development and clinical testing of...

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Autores principales: Xu, Yuexin, Morales, Alicia J., Cargill, Michael J., Towlerton, Andrea M. H., Coffey, David G., Warren, Edus H., Tykodi, Scott S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877496/
https://www.ncbi.nlm.nih.gov/pubmed/31686124
http://dx.doi.org/10.1007/s00262-019-02419-4
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author Xu, Yuexin
Morales, Alicia J.
Cargill, Michael J.
Towlerton, Andrea M. H.
Coffey, David G.
Warren, Edus H.
Tykodi, Scott S.
author_facet Xu, Yuexin
Morales, Alicia J.
Cargill, Michael J.
Towlerton, Andrea M. H.
Coffey, David G.
Warren, Edus H.
Tykodi, Scott S.
author_sort Xu, Yuexin
collection PubMed
description 5T4 (trophoblast glycoprotein, TPBG) is a transmembrane tumor antigen expressed on more than 90% of primary renal cell carcinomas (RCC) and a wide range of human carcinomas but not on most somatic adult tissues. The favorable expression pattern has encouraged the development and clinical testing of 5T4-targeted antibody and vaccine therapies. 5T4 also represents a compelling and unexplored target for T-cell receptor (TCR)-engineered T-cell therapy. Our group has previously isolated high-avidity CD8(+) T-cell clones specific for an HLA-A2-restricted 5T4 epitope (residues 17–25; 5T4(p17)). In this report, targeted single-cell RNA sequencing was performed on 5T4(p17)-specific T-cell clones to sequence the highly variable complementarity-determining region 3 (CDR3) of T-cell receptor α chain (TRA) and β chain (TRB) genes. Full-length TRA and TRB sequences were cloned into lentiviral vectors and transduced into CD8(+) T-cells from healthy donors. Redirected effector T-cell function against 5T4(p17) was measured by cytotoxicity and cytokine release assays. Seven unique TRA-TRB pairs were identified. All seven TCRs exhibited high expression on CD8(+) T-cells with transduction efficiencies from 59 to 89%. TCR-transduced CD8(+) T-cells demonstrated redirected cytotoxicity and cytokine release in response to 5T4(p17) on target-cells and killed 5T4(+)/HLA-A2(+) kidney-, breast-, and colorectal-tumor cell lines as well as primary RCC tumor cells in vitro. TCR-transduced CD8(+) T-cells also detected presentation of 5T4(p17) in TAP1/2-deficient T2 target-cells. TCR-transduced T-cells redirected to recognize the 5T4(p17) epitope from a broadly shared tumor antigen are of interest for future testing as a cellular immunotherapy strategy for HLA-A2(+) subjects with 5T4(+) tumors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-019-02419-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-68774962019-12-10 Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma Xu, Yuexin Morales, Alicia J. Cargill, Michael J. Towlerton, Andrea M. H. Coffey, David G. Warren, Edus H. Tykodi, Scott S. Cancer Immunol Immunother Original Article 5T4 (trophoblast glycoprotein, TPBG) is a transmembrane tumor antigen expressed on more than 90% of primary renal cell carcinomas (RCC) and a wide range of human carcinomas but not on most somatic adult tissues. The favorable expression pattern has encouraged the development and clinical testing of 5T4-targeted antibody and vaccine therapies. 5T4 also represents a compelling and unexplored target for T-cell receptor (TCR)-engineered T-cell therapy. Our group has previously isolated high-avidity CD8(+) T-cell clones specific for an HLA-A2-restricted 5T4 epitope (residues 17–25; 5T4(p17)). In this report, targeted single-cell RNA sequencing was performed on 5T4(p17)-specific T-cell clones to sequence the highly variable complementarity-determining region 3 (CDR3) of T-cell receptor α chain (TRA) and β chain (TRB) genes. Full-length TRA and TRB sequences were cloned into lentiviral vectors and transduced into CD8(+) T-cells from healthy donors. Redirected effector T-cell function against 5T4(p17) was measured by cytotoxicity and cytokine release assays. Seven unique TRA-TRB pairs were identified. All seven TCRs exhibited high expression on CD8(+) T-cells with transduction efficiencies from 59 to 89%. TCR-transduced CD8(+) T-cells demonstrated redirected cytotoxicity and cytokine release in response to 5T4(p17) on target-cells and killed 5T4(+)/HLA-A2(+) kidney-, breast-, and colorectal-tumor cell lines as well as primary RCC tumor cells in vitro. TCR-transduced CD8(+) T-cells also detected presentation of 5T4(p17) in TAP1/2-deficient T2 target-cells. TCR-transduced T-cells redirected to recognize the 5T4(p17) epitope from a broadly shared tumor antigen are of interest for future testing as a cellular immunotherapy strategy for HLA-A2(+) subjects with 5T4(+) tumors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-019-02419-4) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2019-11-04 2019 /pmc/articles/PMC6877496/ /pubmed/31686124 http://dx.doi.org/10.1007/s00262-019-02419-4 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Xu, Yuexin
Morales, Alicia J.
Cargill, Michael J.
Towlerton, Andrea M. H.
Coffey, David G.
Warren, Edus H.
Tykodi, Scott S.
Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma
title Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma
title_full Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma
title_fullStr Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma
title_full_unstemmed Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma
title_short Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma
title_sort preclinical development of t-cell receptor-engineered t-cell therapy targeting the 5t4 tumor antigen on renal cell carcinoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877496/
https://www.ncbi.nlm.nih.gov/pubmed/31686124
http://dx.doi.org/10.1007/s00262-019-02419-4
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