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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
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.
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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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