靶向GDNF家族受体α4的甲状腺髓样癌过继性T细胞免疫疗法,Molecular Therapy: Oncology

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靶向GDNF家族受体α4的甲状腺髓样癌过继性T细胞免疫疗法
Molecular Therapy: Oncology ( IF 5.3 ) Pub Date : 2021-01-26 , DOI: 10.1016/j.omto.2021.01.012
Vijay G Bhoj _{1,

2} , Lucy Li _{1,

2} , Kalpana Parvathaneni _{1,

2} , Zheng Zhang _{1,

2} , Stephen Kacir ₁ , Dimitrios Arhontoulis _{1,

2} , Kenneth Zhou _{1,

2} , Bevin McGettigan-Croce _{1,

2} , Selene Nunez-Cruz _{1,

2} , Gayathri Gulendran _{1,

2} , Alina C Boesteanu ₂ , Laura Johnson ₂ , Michael D Feldman ₁ , Enrico Radaelli ₃ , Keith Mansfield ₄ , MacLean Nasrallah ₁ , Rebecca S Goydel ₅ , Haiyong Peng ₅ , Christoph Rader ₅ , Michael C Milone _{1,

2} , Don L Siegel _{1,

2}

Affiliation

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%，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) 的过继性 T 细胞免疫疗法在癌症治疗中显示出令人鼓舞的结果，但开发受到合适靶抗原可用性的挑战。我们将胶质源性神经营养因子 (GDNF) 家族受体 α 4 (GFRα4) 确定为基于 CAR 的 MTC 治疗的推定抗原靶点。我们显示 GFRα4 在 MTC、MTC 起源的甲状腺内的滤泡旁细胞和正常胸腺中高度表达。我们通过抗体噬菌体展示分离了两个靶向 GFRα4 亚型 a 和 b 的单链可变片段 (scFvs)。使用这些 GFRα4 特异性 scFv 构建了带有 CD3ζ 和 CD137 共刺激结构域的 CAR。GFRα4 特异性 CAR T 触发抗原依赖性细胞毒性和细胞因子产生在体外，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，并支持该抗原作为过继性 T 细胞免疫疗法和其他基于抗体的 MTC 疗法的有希望的靶标。

"点击查看英文标题和摘要"

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 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.

更新日期：2021-02-09

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