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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1256491/full |
| _version_ | 1797635053823459328 |
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| author | Milena Kalaitsidou Owen R. Moon Martina Sykorova Leyuan Bao Yun Qu Sujita Sukumaran Michael Valentine Xingliang Zhou Veethika Pandey Kay Foos Sergey Medvedev Daniel J. Powell Jr Akshata Udyavar Eric Gschweng Ruben Rodriguez Mark E. Dudley Robert E. Hawkins Gray Kueberuwa John S. Bridgeman |
| author_facet | Milena Kalaitsidou Owen R. Moon Martina Sykorova Leyuan Bao Yun Qu Sujita Sukumaran Michael Valentine Xingliang Zhou Veethika Pandey Kay Foos Sergey Medvedev Daniel J. Powell Jr Akshata Udyavar Eric Gschweng Ruben Rodriguez Mark E. Dudley Robert E. Hawkins Gray Kueberuwa John S. Bridgeman |
| author_sort | Milena Kalaitsidou |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T12:16:47Z |
| format | Article |
| id | doaj.art-7f1e15ebf5834e83a34fa2733d953fd0 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T12:16:47Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-7f1e15ebf5834e83a34fa2733d953fd02023-11-07T07:49:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-11-011410.3389/fimmu.2023.12564911256491Signaling via a CD28/CD40 chimeric costimulatory antigen receptor (CoStAR™), targeting folate receptor alpha, enhances T cell activity and augments tumor reactivity of tumor infiltrating lymphocytesMilena Kalaitsidou0Owen R. Moon1Martina Sykorova2Leyuan Bao3Yun Qu4Sujita Sukumaran5Michael Valentine6Xingliang Zhou7Veethika Pandey8Kay Foos9Sergey Medvedev10Daniel J. Powell Jr11Akshata Udyavar12Eric Gschweng13Ruben Rodriguez14Mark E. Dudley15Robert E. Hawkins16Gray Kueberuwa17John S. Bridgeman18Department of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United StatesOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United StatesOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United StatesOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesDepartment of Research, Instil Bio, Dallas, TX, United StatesTransfer 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1256491/fulltumor infiltrating lymphocytes (TIL)folate receptor (FR)scFvchimeric receptorCD28CD40 |
| spellingShingle | Milena Kalaitsidou Owen R. Moon Martina Sykorova Leyuan Bao Yun Qu Sujita Sukumaran Michael Valentine Xingliang Zhou Veethika Pandey Kay Foos Sergey Medvedev Daniel J. Powell Jr Akshata Udyavar Eric Gschweng Ruben Rodriguez Mark E. Dudley Robert E. Hawkins Gray Kueberuwa John S. Bridgeman 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 Frontiers in Immunology tumor infiltrating lymphocytes (TIL) folate receptor (FR) scFv chimeric receptor CD28 CD40 |
| 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 | tumor infiltrating lymphocytes (TIL) folate receptor (FR) scFv chimeric receptor CD28 CD40 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1256491/full |
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