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Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting
Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406808/ https://www.ncbi.nlm.nih.gov/pubmed/37550294 http://dx.doi.org/10.1038/s41467-023-40115-1 |
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author | Lee, Eric Hee Jun Murad, John P. Christian, Lea Gibson, Jackson Yamaguchi, Yukiko Cullen, Cody Gumber, Diana Park, Anthony K. Young, Cari Monroy, Isabel Yang, Jason Stern, Lawrence A. Adkins, Lauren N. Dhapola, Gaurav Gittins, Brenna Chang, Wen-Chung Martinez, Catalina Woo, Yanghee Cristea, Mihaela Rodriguez-Rodriguez, Lorna Ishihara, Jun Lee, John K. Forman, Stephen J. Wang, Leo D. Priceman, Saul J. |
author_facet | Lee, Eric Hee Jun Murad, John P. Christian, Lea Gibson, Jackson Yamaguchi, Yukiko Cullen, Cody Gumber, Diana Park, Anthony K. Young, Cari Monroy, Isabel Yang, Jason Stern, Lawrence A. Adkins, Lauren N. Dhapola, Gaurav Gittins, Brenna Chang, Wen-Chung Martinez, Catalina Woo, Yanghee Cristea, Mihaela Rodriguez-Rodriguez, Lorna Ishihara, Jun Lee, John K. Forman, Stephen J. Wang, Leo D. Priceman, Saul J. |
author_sort | Lee, Eric Hee Jun |
collection | PubMed |
description | Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease. |
format | Online Article Text |
id | pubmed-10406808 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104068082023-08-09 Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting Lee, Eric Hee Jun Murad, John P. Christian, Lea Gibson, Jackson Yamaguchi, Yukiko Cullen, Cody Gumber, Diana Park, Anthony K. Young, Cari Monroy, Isabel Yang, Jason Stern, Lawrence A. Adkins, Lauren N. Dhapola, Gaurav Gittins, Brenna Chang, Wen-Chung Martinez, Catalina Woo, Yanghee Cristea, Mihaela Rodriguez-Rodriguez, Lorna Ishihara, Jun Lee, John K. Forman, Stephen J. Wang, Leo D. Priceman, Saul J. Nat Commun Article Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease. Nature Publishing Group UK 2023-08-07 /pmc/articles/PMC10406808/ /pubmed/37550294 http://dx.doi.org/10.1038/s41467-023-40115-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lee, Eric Hee Jun Murad, John P. Christian, Lea Gibson, Jackson Yamaguchi, Yukiko Cullen, Cody Gumber, Diana Park, Anthony K. Young, Cari Monroy, Isabel Yang, Jason Stern, Lawrence A. Adkins, Lauren N. Dhapola, Gaurav Gittins, Brenna Chang, Wen-Chung Martinez, Catalina Woo, Yanghee Cristea, Mihaela Rodriguez-Rodriguez, Lorna Ishihara, Jun Lee, John K. Forman, Stephen J. Wang, Leo D. Priceman, Saul J. Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting |
title | Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting |
title_full | Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting |
title_fullStr | Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting |
title_full_unstemmed | Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting |
title_short | Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting |
title_sort | antigen-dependent il-12 signaling in car t cells promotes regional to systemic disease targeting |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406808/ https://www.ncbi.nlm.nih.gov/pubmed/37550294 http://dx.doi.org/10.1038/s41467-023-40115-1 |
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