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A novel PD-L1-targeted shark V(NAR) single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer
Chimeric antigen receptor (CAR)-T cell therapy shows excellent potency against hematological malignancies, but it remains challenging to treat solid tumors, mainly because of a lack of appropriate antigenic targets and an immunosuppressive tumor microenvironment (TME). The checkpoint molecule progra...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917269/ https://www.ncbi.nlm.nih.gov/pubmed/35317524 http://dx.doi.org/10.1016/j.omto.2022.02.015 |
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author | Li, Dan English, Hejiao Hong, Jessica Liang, Tianyuzhou Merlino, Glenn Day, Chi-Ping Ho, Mitchell |
author_facet | Li, Dan English, Hejiao Hong, Jessica Liang, Tianyuzhou Merlino, Glenn Day, Chi-Ping Ho, Mitchell |
author_sort | Li, Dan |
collection | PubMed |
description | Chimeric antigen receptor (CAR)-T cell therapy shows excellent potency against hematological malignancies, but it remains challenging to treat solid tumors, mainly because of a lack of appropriate antigenic targets and an immunosuppressive tumor microenvironment (TME). The checkpoint molecule programmed death-ligand 1 (PD-L1) is widely overexpressed in multiple tumor types, and the programmed death-ligand 1 (PD-1)/PD-L1 interaction is a crucial mediator of immunosuppression in the TME. Here we constructed a semi-synthetic shark V(NAR) phage library and isolated anti-PD-L1 single-domain antibodies. Among these V(NAR)s, B2 showed cross-reactivity to human, mouse, and canine PD-L1, and it partially blocked the interaction of human PD-1 with PD-L1. CAR (B2) T cells specifically lysed human breast cancer and liver cancer cells by targeting constitutive and inducible expression of PD-L1 and hindered tumor metastasis. Combination of PD-L1 CAR (B2) T cells with CAR T cells targeted by GPC3 (a liver cancer-specific antigen) regresses liver tumors in mice. We concluded that PD-L1-targeted shark V(NAR) single-domain-based CAR-T therapy is a novel strategy to treat breast and liver cancer. This study provides a rationale for potential use of PD-L1 CAR-T cells as a monotherapy or in combination with a tumor-specific therapy in clinical studies. |
format | Online Article Text |
id | pubmed-8917269 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-89172692022-03-21 A novel PD-L1-targeted shark V(NAR) single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer Li, Dan English, Hejiao Hong, Jessica Liang, Tianyuzhou Merlino, Glenn Day, Chi-Ping Ho, Mitchell Mol Ther Oncolytics Original Article Chimeric antigen receptor (CAR)-T cell therapy shows excellent potency against hematological malignancies, but it remains challenging to treat solid tumors, mainly because of a lack of appropriate antigenic targets and an immunosuppressive tumor microenvironment (TME). The checkpoint molecule programmed death-ligand 1 (PD-L1) is widely overexpressed in multiple tumor types, and the programmed death-ligand 1 (PD-1)/PD-L1 interaction is a crucial mediator of immunosuppression in the TME. Here we constructed a semi-synthetic shark V(NAR) phage library and isolated anti-PD-L1 single-domain antibodies. Among these V(NAR)s, B2 showed cross-reactivity to human, mouse, and canine PD-L1, and it partially blocked the interaction of human PD-1 with PD-L1. CAR (B2) T cells specifically lysed human breast cancer and liver cancer cells by targeting constitutive and inducible expression of PD-L1 and hindered tumor metastasis. Combination of PD-L1 CAR (B2) T cells with CAR T cells targeted by GPC3 (a liver cancer-specific antigen) regresses liver tumors in mice. We concluded that PD-L1-targeted shark V(NAR) single-domain-based CAR-T therapy is a novel strategy to treat breast and liver cancer. This study provides a rationale for potential use of PD-L1 CAR-T cells as a monotherapy or in combination with a tumor-specific therapy in clinical studies. American Society of Gene & Cell Therapy 2022-02-20 /pmc/articles/PMC8917269/ /pubmed/35317524 http://dx.doi.org/10.1016/j.omto.2022.02.015 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Article Li, Dan English, Hejiao Hong, Jessica Liang, Tianyuzhou Merlino, Glenn Day, Chi-Ping Ho, Mitchell A novel PD-L1-targeted shark V(NAR) single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
title | A novel PD-L1-targeted shark V(NAR) single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
title_full | A novel PD-L1-targeted shark V(NAR) single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
title_fullStr | A novel PD-L1-targeted shark V(NAR) single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
title_full_unstemmed | A novel PD-L1-targeted shark V(NAR) single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
title_short | A novel PD-L1-targeted shark V(NAR) single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer |
title_sort | novel pd-l1-targeted shark v(nar) single-domain-based car-t cell strategy for treating breast cancer and liver cancer |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917269/ https://www.ncbi.nlm.nih.gov/pubmed/35317524 http://dx.doi.org/10.1016/j.omto.2022.02.015 |
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