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IGF1R-和ROR1特定CAR-T细胞是高危肉瘤的一个潜在疗法

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发表于 2015-8-25 09:52:06 | 显示全部楼层 |阅读模式
IGF1R- and ROR1-Specific CART Cells as a Potential Therapy for High Risk Sarcomas
IGF1R-ROR1特定CAR-T细胞是高危肉瘤的一个潜在疗法
Patients with metastatic or recurrent and refractorysarcomas have a dismal prognosis. Therefore, new targeted therapies areurgently needed. This study was designed to evaluate chimeric antigen receptor(CAR) T cells targeting the type I insulin-like growth factor receptor (IGF1R)or tyrosine kinase-like orphan receptor 1 (ROR1) molecules for theirtherapeutic potential against sarcomas. Here, we report that IGF1R (15/15) andROR1 (11/15) were highly expressed in sarcoma cell lines including Ewing sarcoma,osteosarcoma, alveolar or embryonalrhabdomyosarcoma, and fibrosarcoma. IGF1Rand ROR1 CAR T cells derived from eight healthy donors using the (SB)transposon system were cytotoxic against sarcoma cells and produced high levelsof IFN-γ, TNF-α and IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR Tcells generated from three sarcoma patients released significant amounts ofIFN-γ in response to sarcoma stimulation. The adoptive transfer of IGF1R andROR1 CAR T cells derived from a sarcoma patient significantly reduced tumorgrowth in pre-established, systemically disseminated and localized osteosarcomaxenograft models in NSG mice. Infusion of IGF1R and ROR1 CAR T cells alsoprolonged animal survival in a localized sarcoma model using NOD/scid mice. Ourdata indicate that both IGF1R and ROR1 can be effectively targeted by SBmodified CAR T cells and that such CAR T cells may be useful in the treatmentof high risk sarcomapatients.
患有转移性或复发和难治肉瘤的患者有一预后结果较差。因此,我们迫切需要新的有针对性的治疗。此研究的目的是评估嵌合抗原受体(CAR)靶向I型胰岛素样生长因子受体(IGF1R)或酪氨酸激酶受体1ROR1)分子治疗肉瘤的潜力。我们报告指出,IGF1R15/15)和ROR111/15)在肉瘤细胞系中有很高的表达率,这些肉瘤细胞系包括尤文肉瘤,骨肉瘤,肺泡或胚胎性横纹肌肉瘤,纤维肉瘤。利用SleepingBeauty系统将八名志愿者的免疫细胞构建的 IGF1R/ ROR1 CAR-T对肉瘤细胞具有细胞毒性,并且以抗原特异性方式产生高水平的IFN-γ,TNF-α和IL-13;而来源于三个肉瘤患者的IGF1RROR1 CAR T细胞响应肉瘤的刺激并释放显著量的IFN-γ。同时利用来自肉瘤患者的IGF1RROR1 CAR-T细胞可显著降低在NSG小鼠骨肉瘤模型中的肿瘤生长率;同时可延长NOD/ SCID小鼠寿命。我们的数据表明,IGF1RROR1可作为利用sleeping beauty 构建的CAR-T有效靶点,并且这种CAR-T细胞有可能会在高危肉瘤患者的治疗中起到重要作用。

IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas.pdf

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