肿瘤细胞治疗研究
英文原题：Oncostatin-M ligand-based CAR-T therapy displays robust anti-tumor activity against osteosarcoma.
Oncostatin-M ligand-based CAR-T therapy displays robust anti-tumor activity against osteosarcoma.
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基于人配体的 OSM CAR-T 细胞对多种骨肉瘤细胞系和患者样本显示出抗肿瘤效果。这些效果在体外、异种移植模型以及模拟转移性疾病的模型中得到了证实。总体而言，这些数据支持继续研究 OSM-CAR-T 细胞作为骨肉瘤新治疗途径。
CAR-T 疗法已经彻底改变了许多血液系统恶性肿瘤的治疗，但其对实体瘤的疗效却远不如前者。实体瘤疗效较低的一个原因是抗原异质性增加。本研究采用基于配体的 CAR-T 方法，该方法允许通过单一配体靶向多个受体。在骨肉瘤细胞系和患者样本中观察到配体制瘤素 M（OSM）的受体、制瘤素 M 受体（OSMR）和/或白血病抑制因子受体（LIFR）的高表达。骨肉瘤是一种骨癌，其治疗方案已停滞近 40 年。因此，本研究探讨基于 OSM 配体的 CAR-T 细胞对骨肉瘤的治疗潜力。
第三代CAR-T 细胞被创建为在其表面表达人OSM，并通过流式细胞术确认了OSM的表面表达。在体外将OSM CAR与骨肉瘤共孵育，通过Incucyte评估细胞死亡，并通过流式细胞术检测PI。将CAR-T 细胞静脉注射到具有骨肉瘤细胞系异种移植瘤和转移性骨肉瘤的小鼠中。对新获得的患者来源样本检测了OSMR和LIFR表达以及对OSM CAR-T 细胞的易感性。对来自一名转移性难治性骨肉瘤患者的新PDX模型（命名为KKOS）进行了表征，并检测了其对OSM CAR-T 细胞的敏感性。所有体内细胞毒性实验每组每次实验均使用n=3-6只小鼠。
OSM-CAR-T 细胞在体外和体内对表达OSM任一受体的骨肉瘤细胞系和患者样本显示出细胞毒性。以靶标特异性方式观察到细胞因子释放的大幅增加，特别是IFN。静脉注射一次OSM-CAR-T 细胞即可减轻两种不同小鼠异种移植模型中的肿瘤负荷。在转移模型和植入多个KKOS肿瘤的小鼠模型中也观察到类似的抗肿瘤效果。
CAR-T therapy has revolutionized treatments for many hematologic malignancies, but it has shown far less efficacy against solid tumors. One reason for this lower efficacy in solid tumors is increased antigen heterogeneity. This study utilizes a ligand-based CAR-T approach, which allows targeting of multiple receptors by a single ligand. A high expression of the ligand oncostatin M's (OSM) receptors, oncostatin M receptor (OSMR), and/or leukemic inhibitory factor receptor (LIFR) were noted in osteosarcoma cell lines and patient samples. Osteosarcoma is a bone cancer where treatment options have been stagnant for close to 40 years. Thus, this study explores the therapeutic potential of OSM ligand-based CAR-T cells against osteosarcoma.
Third-generation CAR-T cells expressing human OSM on their surface were created, with the surface expression of OSM confirmed by flow cytometry. Co-incubation of OSM CARs and osteosarcoma in vitro was performed, with cell death assessed via Incucyte and PI detection by flow cytometry. CAR-Ts were injected i.v. into mice with osteosarcoma cell line xenografts, and metastatic osteosarcoma. New patient-derived samples were tested for OSMR and LIFR expression and vulnerability to OSM CAR T cells. A new PDX model (named KKOS) from a patient with metastatic treatment-resistant osteosarcoma was characterized and tested for its susceptibility to OSM CAR T cells. All cytotoxic in vivo experiments were performed with n=3-6 mice per group per experiment.
OSM-CAR-T cells displayed cytotoxicity against osteosarcoma cell lines and patient samples expressing either one of OSM's receptors in vitro and in vivo. Large increases in cytokine release, specifically IFN , were noted in a target-specific manner. One injection of OSM-CAR-T cells intravenously reduced tumor burden in two different mouse xenograft models. A similar anti-tumor effect was also noted in a metastatic model and a mouse model with multiple implanted KKOS tumors.
Human ligand-based OSM CAR-T cells displayed anti-tumor effects against multiple osteosarcoma cell lines and patient samples. These effects were demonstrated in vitro, in xenograft models, and against a model simulating metastatic disease. Overall, this data supports the continued study of OSM-CAR-T cells as a new therapeutic avenue for osteosarcoma.
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