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Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes
Transfer of autologous tumor infiltrating lymphocytes (TIL) to patients with refractory melanoma has shown clinical efficacy in a number of trials. However, extending the clinical benefit to patients with other cancers poses a challenge. Inefficient costimulation in the tumor microenvironment can le...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664248/ https://www.ncbi.nlm.nih.gov/pubmed/38022678 http://dx.doi.org/10.3389/fimmu.2023.1256491 |
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author | Kalaitsidou, Milena Moon, Owen R. Sykorova, Martina Bao, Leyuan Qu, Yun Sukumaran, Sujita Valentine, Michael Zhou, Xingliang Pandey, Veethika Foos, Kay Medvedev, Sergey Powell Jr, Daniel J. Udyavar, Akshata Gschweng, Eric Rodriguez, Ruben Dudley, Mark E. Hawkins, Robert E. Kueberuwa, Gray Bridgeman, John S. |
author_facet | Kalaitsidou, Milena Moon, Owen R. Sykorova, Martina Bao, Leyuan Qu, Yun Sukumaran, Sujita Valentine, Michael Zhou, Xingliang Pandey, Veethika Foos, Kay Medvedev, Sergey Powell Jr, Daniel J. Udyavar, Akshata Gschweng, Eric Rodriguez, Ruben Dudley, Mark E. Hawkins, Robert E. Kueberuwa, Gray Bridgeman, John S. |
author_sort | Kalaitsidou, Milena |
collection | PubMed |
description | Transfer of autologous tumor infiltrating lymphocytes (TIL) to patients with refractory melanoma has shown clinical efficacy in a number of trials. However, extending the clinical benefit to patients with other cancers poses a challenge. Inefficient costimulation in the tumor microenvironment can lead to T cell anergy and exhaustion resulting in poor anti-tumor activity. Here, we describe a chimeric costimulatory antigen receptor (CoStAR) comprised of FRα-specific scFv linked to CD28 and CD40 intracellular signaling domains. CoStAR signaling alone does not activate T cells, while the combination of TCR and CoStAR signaling enhances T cell activity resulting in less differentiated T cells, and augmentation of T cell effector functions, including cytokine secretion and cytotoxicity. CoStAR activity resulted in superior T cell proliferation, even in the absence of exogenous IL-2. Using an in vivo transplantable tumor model, CoStAR was shown to improve T cell survival after transfer, enhanced control of tumor growth, and improved host survival. CoStAR could be reliably engineered into TIL from multiple tumor indications and augmented TIL activity against autologous tumor targets both in vitro and in vivo. CoStAR thus represents a general approach to improving TIL therapy with synthetic costimulation. |
format | Online Article Text |
id | pubmed-10664248 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-106642482023-01-01 Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes Kalaitsidou, Milena Moon, Owen R. Sykorova, Martina Bao, Leyuan Qu, Yun Sukumaran, Sujita Valentine, Michael Zhou, Xingliang Pandey, Veethika Foos, Kay Medvedev, Sergey Powell Jr, Daniel J. Udyavar, Akshata Gschweng, Eric Rodriguez, Ruben Dudley, Mark E. Hawkins, Robert E. Kueberuwa, Gray Bridgeman, John S. Front Immunol Immunology Transfer of autologous tumor infiltrating lymphocytes (TIL) to patients with refractory melanoma has shown clinical efficacy in a number of trials. However, extending the clinical benefit to patients with other cancers poses a challenge. Inefficient costimulation in the tumor microenvironment can lead to T cell anergy and exhaustion resulting in poor anti-tumor activity. Here, we describe a chimeric costimulatory antigen receptor (CoStAR) comprised of FRα-specific scFv linked to CD28 and CD40 intracellular signaling domains. CoStAR signaling alone does not activate T cells, while the combination of TCR and CoStAR signaling enhances T cell activity resulting in less differentiated T cells, and augmentation of T cell effector functions, including cytokine secretion and cytotoxicity. CoStAR activity resulted in superior T cell proliferation, even in the absence of exogenous IL-2. Using an in vivo transplantable tumor model, CoStAR was shown to improve T cell survival after transfer, enhanced control of tumor growth, and improved host survival. CoStAR could be reliably engineered into TIL from multiple tumor indications and augmented TIL activity against autologous tumor targets both in vitro and in vivo. CoStAR thus represents a general approach to improving TIL therapy with synthetic costimulation. Frontiers Media S.A. 2023-11-07 /pmc/articles/PMC10664248/ /pubmed/38022678 http://dx.doi.org/10.3389/fimmu.2023.1256491 Text en Copyright © 2023 Kalaitsidou, Moon, Sykorova, Bao, Qu, Sukumaran, Valentine, Zhou, Pandey, Foos, Medvedev, Powell Jr, Udyavar, Gschweng, Rodriguez, Dudley, Hawkins, Kueberuwa and Bridgeman 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 Kalaitsidou, Milena Moon, Owen R. Sykorova, Martina Bao, Leyuan Qu, Yun Sukumaran, Sujita Valentine, Michael Zhou, Xingliang Pandey, Veethika Foos, Kay Medvedev, Sergey Powell Jr, Daniel J. Udyavar, Akshata Gschweng, Eric Rodriguez, Ruben Dudley, Mark E. Hawkins, Robert E. Kueberuwa, Gray Bridgeman, John S. Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes |
title | Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes |
title_full | Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes |
title_fullStr | Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes |
title_full_unstemmed | Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes |
title_short | Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytes |
title_sort | signaling via a cd28/cd40 chimeric costimulatory antigen receptor (costar™), targeting folate receptor alpha, enhances t cell activity and augments tumor reactivity of tumor infiltrating lymphocytes |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664248/ https://www.ncbi.nlm.nih.gov/pubmed/38022678 http://dx.doi.org/10.3389/fimmu.2023.1256491 |
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