Adoptive T cell immunotherapy for medullary thyroid carcinoma targeting GDNF family receptor alpha 4
| Autor: | Selene Nunez-Cruz, Michael Feldman, Kenneth Zhou, Christoph Rader, Haiyong Peng, Stephen Kacir, Keith Mansfield, Alina C. Boesteanu, Zheng Zhang, Enrico Radaelli, MacLean Nasrallah, Bevin McGettigan-Croce, Rebecca S. Goydel, Vijay Bhoj, Don L. Siegel, Michael C. Milone, Kalpana Parvathaneni, Gayathri Gulendran, Dimitrios Arhontoulis, Lucy Z. Li, Laura A. Johnson |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research endocrine system diseases medicine.medical_treatment lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine Antigen medicine Glial cell line-derived neurotrophic factor Medullary thyroid carcinoma Pharmacology (medical) CAR T cells biology business.industry CD137 Cancer Medullary thyroid cancer Immunotherapy GFRa4 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Chimeric antigen receptor 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Molecular Medicine Original Article immunotherapy Antibody business RETMC |
| Zdroj: | Molecular Therapy Oncolytics Molecular Therapy: Oncolytics, Vol 20, Iss, Pp 387-398 (2021) |
| ISSN: | 2372-7705 |
| Popis: | 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. Graphical Abstract Metastatic medullary thyroid carcinoma (MTC) is a rare but aggressive malignancy with no curative options. By sequencing mRNA from a patient’s tumor, Siegel and colleagues identified and characterized GFRα4 as a promising tumor target antigen and demonstrated that CAR T immunotherapy targeting this antigen controlled MTC in tumor xenograft models. |
| Databáze: | OpenAIRE |
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