Bhoj Vijay G, Li Lucy, Parvathaneni Kalpana, Zhang Zheng, Kacir Stephen, Arhontoulis Dimitrios, Zhou Kenneth, McGettigan-Croce Bevin, Nunez-Cruz Selene, Gulendran Gayathri, Boesteanu Alina C, Johnson Laura, Feldman Michael D, Radaelli Enrico, Mansfield Keith, Nasrallah MacLean, Goydel Rebecca S, Peng Haiyong, Rader Christoph, Milone Michael C, Siegel Don L
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, USA.
Mol Ther Oncolytics. 2021 Jan 26;20:387-398. doi: 10.1016/j.omto.2021.01.012. eCollection 2021 Mar 26.
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 , 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.
转移性甲状腺髓样癌（MTC）是一种罕见但通常具有侵袭性的甲状腺恶性肿瘤，其5年生存率低于40%，且有效的治疗选择很少。使用嵌合抗原受体（CAR）修饰的T细胞（CAR T细胞）进行过继性T细胞免疫疗法在癌症治疗中显示出令人鼓舞的结果，但合适靶抗原的可用性给其发展带来了挑战。我们确定胶质细胞源性神经营养因子（GDNF）家族受体α4（GFRα4）作为基于CAR的MTC治疗的假定抗原靶点。我们发现GFRα4在MTC、MTC起源的甲状腺内滤泡旁细胞以及正常胸腺中高表达。通过抗体噬菌体展示，我们分离出了两个靶向GFRα4亚型a和b的单链可变片段（scFv）。使用这些GFRα4特异性scFv构建了携带CD3ζ和CD137共刺激结构域的CAR。GFRα4特异性CAR T细胞触发抗原依赖性细胞毒性和细胞因子产生，并且它们能够在MTC的免疫缺陷小鼠异种移植模型中消除源自MTC TT细胞系的肿瘤。这些数据证明了通过CAR T靶向GFRα4的可行性，并支持该抗原作为MTC过继性T细胞免疫疗法和其他基于抗体疗法的有前景的靶点。
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