Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, Guangzhou, China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Cancer. 2020 May 1;126 Suppl 9:2093-2100. doi: 10.1002/cncr.32764.
New immunotherapeutic approaches are urgently needed for metastatic rhabdomyosarcoma, which is associated with poor survival and unsatisfactory treatment outcomes. Platelet-derived growth factor receptor α (PDGFRA) plays an essential role in the onset and development of rhabdomyosarcoma and is a new potential therapeutic target for rhabdomyosarcoma. The objective of this study was to generate humanized PDGFRA single-chain variable fragment-based chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) against PDGFRA-positive rhabdomyosarcoma.
PDGFRA antigen expression was evaluated in specimens from patients with rhabdomyosarcoma. CAR-T cells containing a PDGFRA-specific single-chain variable fragment was developed in combination with a 4-1BB costimulatory domain and a CD3-ζ signaling domain. Specific cytotoxic effects of PDGFRA CAR-T cells, T-cell proliferation, and cytokine secretion were investigated in vitro and in vivo.
PDGFRA CAR-T cells produced large amounts of immune-promoting cytokines, including interleukin 2, tumor necrosis factor α, and interferon γ, and exhibited efficient cytotoxic activity toward human PDGFRA-overexpressing rhabdomyosarcoma cells in vitro. In a subcutaneous xenograft model, CAR-T cells were more effective against PDGFRA-overexpressing rhabdomyosarcoma than against rhabdomyosarcoma with low PDGFRA expression in terms of tumor regression and patient survival. Expanded CAR-T cells also were detected in peripheral blood.
The current study demonstrates for the first time that the PDGFRA antigen is a promising target for CAR-T-cell therapy in rhabdomyosarcoma and likely in a wide spectrum of other PDGFRA-expressing cancers.
转移性横纹肌肉瘤的生存预后差，治疗效果不理想，因此迫切需要新的免疫治疗方法。血小板衍生生长因子受体α（PDGFRA）在横纹肌肉瘤的发生和发展中起关键作用，是横纹肌肉瘤新的潜在治疗靶点。本研究旨在构建针对 PDGFRA 阳性横纹肌肉瘤的人源化 PDGFRA 单链可变片段嵌合抗原受体（CAR）修饰 T 细胞（CAR-T 细胞）。
评估了横纹肌肉瘤患者标本中 PDGFRA 抗原的表达。构建了含有 PDGFRA 特异性单链可变片段的 CAR-T 细胞，该片段与 4-1BB 共刺激结构域和 CD3-ζ 信号结构域融合。在体外和体内研究了 PDGFRA CAR-T 细胞的特异性细胞毒性作用、T 细胞增殖和细胞因子分泌。
PDGFRA CAR-T 细胞产生了大量的免疫促进细胞因子，包括白细胞介素 2、肿瘤坏死因子α和干扰素γ，并在体外对人 PDGFRA 过表达横纹肌肉瘤细胞表现出有效的细胞毒性作用。在皮下异种移植模型中，CAR-T 细胞对 PDGFRA 过表达横纹肌肉瘤的疗效优于对 PDGFRA 低表达横纹肌肉瘤的疗效，表现在肿瘤消退和患者生存方面。在外周血中也检测到扩增的 CAR-T 细胞。
本研究首次证明 PDGFRA 抗原是横纹肌肉瘤 CAR-T 细胞治疗的一个有前途的靶点，可能也是广泛表达 PDGFRA 的其他癌症的一个靶点。
