Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4
Metastatic medullary thyroid cancer (MTC) is a rare but often aggressive thyroid malignancy with a 5-year survival rate of less than 40% and few effective therapeutic options. Adoptive T cell immunotherapy using chimeric antigen receptor (CAR)-modified T cells (CAR Ts) is showing encouraging results...
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Elsevier
2021-03-01
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Series: | Molecular Therapy: Oncolytics |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770521000139 |
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doaj-21295495ac0b4d158ff8bf09829bb9f3 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Vijay G. Bhoj Lucy Li Kalpana Parvathaneni Zheng Zhang Stephen Kacir Dimitrios Arhontoulis Kenneth Zhou Bevin McGettigan-Croce Selene Nunez-Cruz Gayathri Gulendran Alina C. Boesteanu Laura Johnson Michael D. Feldman Enrico Radaelli Keith Mansfield MacLean Nasrallah Rebecca S. Goydel Haiyong Peng Christoph Rader Michael C. Milone Don L. Siegel |
spellingShingle |
Vijay G. Bhoj Lucy Li Kalpana Parvathaneni Zheng Zhang Stephen Kacir Dimitrios Arhontoulis Kenneth Zhou Bevin McGettigan-Croce Selene Nunez-Cruz Gayathri Gulendran Alina C. Boesteanu Laura Johnson Michael D. Feldman Enrico Radaelli Keith Mansfield MacLean Nasrallah Rebecca S. Goydel Haiyong Peng Christoph Rader Michael C. Milone Don L. Siegel Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4 Molecular Therapy: Oncolytics Medullary thyroid carcinoma immunotherapy GFRa4 CAR T cells RETMC |
author_facet |
Vijay G. Bhoj Lucy Li Kalpana Parvathaneni Zheng Zhang Stephen Kacir Dimitrios Arhontoulis Kenneth Zhou Bevin McGettigan-Croce Selene Nunez-Cruz Gayathri Gulendran Alina C. Boesteanu Laura Johnson Michael D. Feldman Enrico Radaelli Keith Mansfield MacLean Nasrallah Rebecca S. Goydel Haiyong Peng Christoph Rader Michael C. Milone Don L. Siegel |
author_sort |
Vijay G. Bhoj |
title |
Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4 |
title_short |
Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4 |
title_full |
Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4 |
title_fullStr |
Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4 |
title_full_unstemmed |
Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4 |
title_sort |
adoptive t cell immunotherapy for medullary thyroid carcinoma targeting gdnf family receptor alpha 4 |
publisher |
Elsevier |
series |
Molecular Therapy: Oncolytics |
issn |
2372-7705 |
publishDate |
2021-03-01 |
description |
Metastatic medullary thyroid cancer (MTC) is a rare but often aggressive thyroid malignancy with a 5-year survival rate of less than 40% and few effective therapeutic options. Adoptive T cell immunotherapy using chimeric antigen receptor (CAR)-modified T cells (CAR Ts) is showing encouraging results in the treatment of cancer, but development is challenged by the availability of suitable target antigens. We identified glial-derived neurotrophic factor (GDNF) family receptor alpha 4 (GFRα4) as a putative antigen target for CAR-based therapy of MTC. We show that GFRα4 is highly expressed in MTC, in parafollicular cells within the thyroid from which MTC originates, and in normal thymus. We isolated two single-chain variable fragments (scFvs) targeting GFRα4 isoforms a and b by antibody phage display. CARs bearing the CD3ζ and the CD137 costimulatory domains were constructed using these GFRα4-specific scFvs. GFRα4-specific CAR Ts trigger antigen-dependent cytotoxicity and cytokine production in vitro, and they are able to eliminate tumors derived from the MTC TT cell line in an immunodeficient mouse xenograft model of MTC. These data demonstrate the feasibility of targeting GFRα4 by CAR T and support this antigen as a promising target for adoptive T cell immunotherapy and other antibody-based therapies for MTC. |
topic |
Medullary thyroid carcinoma immunotherapy GFRa4 CAR T cells RETMC |
url |
http://www.sciencedirect.com/science/article/pii/S2372770521000139 |
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doaj-21295495ac0b4d158ff8bf09829bb9f32021-02-11T04:22:02ZengElsevierMolecular Therapy: Oncolytics2372-77052021-03-0120387398Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4Vijay G. Bhoj0Lucy Li1Kalpana Parvathaneni2Zheng Zhang3Stephen Kacir4Dimitrios Arhontoulis5Kenneth Zhou6Bevin McGettigan-Croce7Selene Nunez-Cruz8Gayathri Gulendran9Alina C. Boesteanu10Laura Johnson11Michael D. Feldman12Enrico Radaelli13Keith Mansfield14MacLean Nasrallah15Rebecca S. Goydel16Haiyong Peng17Christoph Rader18Michael C. Milone19Don L. Siegel20Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author: Vijay G. Bhoj, MD, PhD, South Tower Pavilion, 8-111, 3400 Civic Ctr. Blvd., Philadelphia, PA 19104, USA.Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USACenter for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USACenter for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADiscovery and Investigative Pathology, Novartis Institute for Biomedical Research, Cambridge, MA 02139, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USADepartment of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USADepartment of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL 33458, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author: Don L. Siegel, PhD, MD, South Tower Pavilion, 9-112, 3400 Civic Ctr. Blvd., Philadelphia, PA 19104, USA.Metastatic medullary thyroid cancer (MTC) is a rare but often aggressive thyroid malignancy with a 5-year survival rate of less than 40% and few effective therapeutic options. Adoptive T cell immunotherapy using chimeric antigen receptor (CAR)-modified T cells (CAR Ts) is showing encouraging results in the treatment of cancer, but development is challenged by the availability of suitable target antigens. We identified glial-derived neurotrophic factor (GDNF) family receptor alpha 4 (GFRα4) as a putative antigen target for CAR-based therapy of MTC. We show that GFRα4 is highly expressed in MTC, in parafollicular cells within the thyroid from which MTC originates, and in normal thymus. We isolated two single-chain variable fragments (scFvs) targeting GFRα4 isoforms a and b by antibody phage display. CARs bearing the CD3ζ and the CD137 costimulatory domains were constructed using these GFRα4-specific scFvs. GFRα4-specific CAR Ts trigger antigen-dependent cytotoxicity and cytokine production in vitro, and they are able to eliminate tumors derived from the MTC TT cell line in an immunodeficient mouse xenograft model of MTC. These data demonstrate the feasibility of targeting GFRα4 by CAR T and support this antigen as a promising target for adoptive T cell immunotherapy and other antibody-based therapies for MTC.http://www.sciencedirect.com/science/article/pii/S2372770521000139Medullary thyroid carcinomaimmunotherapyGFRa4CAR T cellsRETMC |