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PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies

In spite of impressive success in treating hematologic malignancies, adoptive therapy with chimeric antigen receptor modified T cells (CAR T) has not yet been effective in solid tumors, where identification of suitable tumor-specific antigens remains a major obstacle for CAR T-cell therapy due to th...

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Autores principales: Jie, Yamin, Liu, Guijun, Feng, Lina, Li, Ying, E, Mingyan, Wu, Liangliang, Li, Yinyin, Rong, Guanghua, Li, Yongwu, Wei, Huafeng, Gu, Anxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406764/
https://www.ncbi.nlm.nih.gov/pubmed/34475869
http://dx.doi.org/10.3389/fimmu.2021.665970
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author Jie, Yamin
Liu, Guijun
Feng, Lina
Li, Ying
E, Mingyan
Wu, Liangliang
Li, Yinyin
Rong, Guanghua
Li, Yongwu
Wei, Huafeng
Gu, Anxin
author_facet Jie, Yamin
Liu, Guijun
Feng, Lina
Li, Ying
E, Mingyan
Wu, Liangliang
Li, Yinyin
Rong, Guanghua
Li, Yongwu
Wei, Huafeng
Gu, Anxin
author_sort Jie, Yamin
collection PubMed
description In spite of impressive success in treating hematologic malignancies, adoptive therapy with chimeric antigen receptor modified T cells (CAR T) has not yet been effective in solid tumors, where identification of suitable tumor-specific antigens remains a major obstacle for CAR T-cell therapy due to the “on target off tumor” toxicity. Protein tyrosine kinase 7 (PTK7) is a member of the Wnt-related pseudokinases and identified as a highly expressed antigen enriched in cancer stem cells (CSCs) from multiple solid tumors, including but not limited to triple-negative breast cancer, non-small-cell lung cancer, and ovarian cancer, suggesting it may serve as a promising tumor-specific target for CAR T-cell therapy. In this study, we constructed three different PTK7-specific CAR (PTK7-CAR1/2/3), each comprising a humanized PTK7-specific single-chain variable fragment (scFv), hinge and transmembrane (TM) regions of the human CD8α molecule, 4-1BB intracellular co-stimulatory domain (BB-ICD), and CD3ζ intracellular domain (CD3ζ-ICD) sequence, and then prepared the CAR T cells by lentivirus-mediated transduction of human activated T cells accordingly, and we sequentially evaluated their antigen-specific recognition and killing activity in vitro and in vivo. T cells transduced with all three PTK7-CAR candidates exhibited antigen-specific cytokine production and potent cytotoxicity against naturally expressing PTK7-positive tumor cells of multiple cancer types without mediating cytotoxicity of a panel of normal primary human cells; meanwhile, in vitro recursive cytotoxicity assays demonstrated that only PTK7-CAR2 modified T cells retained effective through multiple rounds of tumor challenge. Using in vivo xenograft models of lung cancers with different expression levels of PTK7, systemic delivery of PTK7-CAR2 modified T cells significantly prevented tumor growth and prolonged overall survival of mice. Altogether, our results support PTK7 as a therapeutic target suitable for CAR T-cell therapy that could be applied for lung cancers and many other solid cancers with PTK7 overexpression.
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spelling pubmed-84067642021-09-01 PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies Jie, Yamin Liu, Guijun Feng, Lina Li, Ying E, Mingyan Wu, Liangliang Li, Yinyin Rong, Guanghua Li, Yongwu Wei, Huafeng Gu, Anxin Front Immunol Immunology In spite of impressive success in treating hematologic malignancies, adoptive therapy with chimeric antigen receptor modified T cells (CAR T) has not yet been effective in solid tumors, where identification of suitable tumor-specific antigens remains a major obstacle for CAR T-cell therapy due to the “on target off tumor” toxicity. Protein tyrosine kinase 7 (PTK7) is a member of the Wnt-related pseudokinases and identified as a highly expressed antigen enriched in cancer stem cells (CSCs) from multiple solid tumors, including but not limited to triple-negative breast cancer, non-small-cell lung cancer, and ovarian cancer, suggesting it may serve as a promising tumor-specific target for CAR T-cell therapy. In this study, we constructed three different PTK7-specific CAR (PTK7-CAR1/2/3), each comprising a humanized PTK7-specific single-chain variable fragment (scFv), hinge and transmembrane (TM) regions of the human CD8α molecule, 4-1BB intracellular co-stimulatory domain (BB-ICD), and CD3ζ intracellular domain (CD3ζ-ICD) sequence, and then prepared the CAR T cells by lentivirus-mediated transduction of human activated T cells accordingly, and we sequentially evaluated their antigen-specific recognition and killing activity in vitro and in vivo. T cells transduced with all three PTK7-CAR candidates exhibited antigen-specific cytokine production and potent cytotoxicity against naturally expressing PTK7-positive tumor cells of multiple cancer types without mediating cytotoxicity of a panel of normal primary human cells; meanwhile, in vitro recursive cytotoxicity assays demonstrated that only PTK7-CAR2 modified T cells retained effective through multiple rounds of tumor challenge. Using in vivo xenograft models of lung cancers with different expression levels of PTK7, systemic delivery of PTK7-CAR2 modified T cells significantly prevented tumor growth and prolonged overall survival of mice. Altogether, our results support PTK7 as a therapeutic target suitable for CAR T-cell therapy that could be applied for lung cancers and many other solid cancers with PTK7 overexpression. Frontiers Media S.A. 2021-08-12 /pmc/articles/PMC8406764/ /pubmed/34475869 http://dx.doi.org/10.3389/fimmu.2021.665970 Text en Copyright © 2021 Jie, Liu, Feng, Li, E, Wu, Li, Rong, Li, Wei and Gu 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
Jie, Yamin
Liu, Guijun
Feng, Lina
Li, Ying
E, Mingyan
Wu, Liangliang
Li, Yinyin
Rong, Guanghua
Li, Yongwu
Wei, Huafeng
Gu, Anxin
PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies
title PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies
title_full PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies
title_fullStr PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies
title_full_unstemmed PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies
title_short PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies
title_sort ptk7-targeting car t-cells for the treatment of lung cancer and other malignancies
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406764/
https://www.ncbi.nlm.nih.gov/pubmed/34475869
http://dx.doi.org/10.3389/fimmu.2021.665970
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