| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Oncolytics, Vol 20, Iss , Pp 387-398 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2372-7705 |
| DOI: |
10.1016/j.omto.2021.01.012 |
| 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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