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Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors

Chimeric antigen receptor (CAR) T cells targeting glypican-3 (GPC3) demonstrated early signs of therapeutic efficacy to hepatocellular carcinoma patients with a risk of cytokine release syndrome (CRS). Several adoptive cell therapies (ACTs) with T cells using the natural T cell receptor (TCR) signal...

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Autores principales: Sun, Yansha, Dong, Yiwei, Sun, Ruixin, Liu, Yifan, Wang, Yi, Luo, Hong, Shi, Bizhi, Jiang, Hua, Li, Zonghai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065615/
https://www.ncbi.nlm.nih.gov/pubmed/35572194
http://dx.doi.org/10.1016/j.omto.2022.04.003
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author Sun, Yansha
Dong, Yiwei
Sun, Ruixin
Liu, Yifan
Wang, Yi
Luo, Hong
Shi, Bizhi
Jiang, Hua
Li, Zonghai
author_facet Sun, Yansha
Dong, Yiwei
Sun, Ruixin
Liu, Yifan
Wang, Yi
Luo, Hong
Shi, Bizhi
Jiang, Hua
Li, Zonghai
author_sort Sun, Yansha
collection PubMed
description Chimeric antigen receptor (CAR) T cells targeting glypican-3 (GPC3) demonstrated early signs of therapeutic efficacy to hepatocellular carcinoma patients with a risk of cytokine release syndrome (CRS). Several adoptive cell therapies (ACTs) with T cells using the natural T cell receptor (TCR) signaling induced more efficient antitumor function and reduced cytokine production relative to CARs in solid tumors. To improve the efficacy and safety of GPC3-targeted ACTs, T cells were modified with anti-GPC3 single-chain fragment variable(sFv) linked to CD3ε, which could be incorporated into the entire TCR/CD3 complex to form chimeric sFv-CD3ε receptor (sFv-ε). sFv-ε T cells showed competitive antitumor activity and lower cytokine release compared to 28ζ or BBζ CAR T cells, which may be ascribed to moderately less activated Ca(2+)-calcineurin-NFAT signaling pathway. We further generated murine sFv-ε T cells with interleukin-7 co-expression (7sFv-ε) to promote T cell survival and to mobilize the endogenous immune system. In immunocompetent mouse models, 7sFv-ε T cells showed superior persistence, antitumor efficacy, and immunological memory while preserving the low production of cytokines associated with CRS compared to conventional sFv-ε T cells. These results indicate that GPC3-specific 7sFv-ε T cells could serve as a promising therapeutic strategy for solid tumors.
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spelling pubmed-90656152022-05-13 Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors Sun, Yansha Dong, Yiwei Sun, Ruixin Liu, Yifan Wang, Yi Luo, Hong Shi, Bizhi Jiang, Hua Li, Zonghai Mol Ther Oncolytics Original Article Chimeric antigen receptor (CAR) T cells targeting glypican-3 (GPC3) demonstrated early signs of therapeutic efficacy to hepatocellular carcinoma patients with a risk of cytokine release syndrome (CRS). Several adoptive cell therapies (ACTs) with T cells using the natural T cell receptor (TCR) signaling induced more efficient antitumor function and reduced cytokine production relative to CARs in solid tumors. To improve the efficacy and safety of GPC3-targeted ACTs, T cells were modified with anti-GPC3 single-chain fragment variable(sFv) linked to CD3ε, which could be incorporated into the entire TCR/CD3 complex to form chimeric sFv-CD3ε receptor (sFv-ε). sFv-ε T cells showed competitive antitumor activity and lower cytokine release compared to 28ζ or BBζ CAR T cells, which may be ascribed to moderately less activated Ca(2+)-calcineurin-NFAT signaling pathway. We further generated murine sFv-ε T cells with interleukin-7 co-expression (7sFv-ε) to promote T cell survival and to mobilize the endogenous immune system. In immunocompetent mouse models, 7sFv-ε T cells showed superior persistence, antitumor efficacy, and immunological memory while preserving the low production of cytokines associated with CRS compared to conventional sFv-ε T cells. These results indicate that GPC3-specific 7sFv-ε T cells could serve as a promising therapeutic strategy for solid tumors. American Society of Gene & Cell Therapy 2022-04-19 /pmc/articles/PMC9065615/ /pubmed/35572194 http://dx.doi.org/10.1016/j.omto.2022.04.003 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Sun, Yansha
Dong, Yiwei
Sun, Ruixin
Liu, Yifan
Wang, Yi
Luo, Hong
Shi, Bizhi
Jiang, Hua
Li, Zonghai
Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors
title Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors
title_full Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors
title_fullStr Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors
title_full_unstemmed Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors
title_short Chimeric anti-GPC3 sFv-CD3ε receptor-modified T cells with IL7 co-expression for the treatment of solid tumors
title_sort chimeric anti-gpc3 sfv-cd3ε receptor-modified t cells with il7 co-expression for the treatment of solid tumors
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065615/
https://www.ncbi.nlm.nih.gov/pubmed/35572194
http://dx.doi.org/10.1016/j.omto.2022.04.003
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