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IGF1R和ROR1靶向CAR T细胞治疗——高危肉瘤潜在的治疗方案

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发表于 2015-11-2 22:15:05 | 显示全部楼层 |阅读模式
IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas
Abstract
Patients with metastatic or recurrent and refractory sarcomas have a dismal prognosis. Therefore, new targeted therapies are urgently 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 their therapeutic potential against sarcomas. Here, we report that IGF1R (15/15) and ROR1 (11/15) were highly expressed in sarcoma cell lines including Ewing sarcoma, osteosarcoma, alveolar or embryonal rhabdomyosarcoma, and fibrosarcoma. IGF1R and ROR1 CAR T cells derived from eight healthy donors using theSleeping Beauty(SB) transposon system were cytotoxic against sarcoma cells and produced high levels of IFN-γ, TNF-αand IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR T cells generated from three sarcoma patients released significant amounts of IFN-γin response to sarcoma stimulation. The adoptive transfer of IGF1R and ROR1 CAR T cells derived from a sarcoma patient significantly reduced tumor growth in pre-established, systemically disseminated and localized osteosarcoma xenograft models in NSG mice. Infusion of IGF1R and ROR1 CAR T cells also prolonged animal survival in a localized sarcoma model using NOD/scid mice. Our data indicate that both IGF1R and ROR1 can be effectively targeted by SB modified CAR T cells and that such CAR T cells may be useful in the treatment of high risk sarcoma patients.
IGF1R和ROR1靶向CAR T细胞治疗——高危肉瘤潜在的治疗方案
目前转移或复发性难治性肉瘤的病人治疗之后的效果非常不满意。因此,新的靶向治疗方案需求非常迫切。这项研究设计用来评估嵌合抗原受体修饰的T细胞分别靶向胰岛素样生长因子I型受体(IGF1R)或孤儿受体酪氨酸激酶1ROR1)分子对肉瘤的治疗潜力。在这里我们报告了IGF1R(15 / 15)和ROR111 / 15)在肉瘤细胞系包括尤文氏肉瘤,骨肉瘤肺泡或胚胎性横纹肌肉瘤,纤维肉瘤中高表达。使用转位系统,来自八名健康人的IGF1RROR1CAR-T细胞对肉瘤产生细胞毒性,并且以抗原特异性的方式产生了高水平的IFN-γ, TNF-αand IL-13. 三名肉瘤患者制备的IGF1RROR1CAR-T细胞对肉瘤的刺激产生大量的干扰素γ。在NSG 小鼠上预先建立的系统扩散的局部成骨肉瘤移植瘤模型中,从一个肉瘤病人体内过继的IGF1R 和ROR1 CAR T细胞治疗能够明显抑制肿瘤的生长。利用局部成骨肉瘤NOD/SCID小鼠模型,IGF1RROR1CAR-T细胞输注能够延长动物的生存期。我们的数据表明,IGF1RROR1通过在T细胞上的修饰,可以有效地针对高风险肉瘤患者,并且这种治疗方式对肉瘤病人是非常有效果的。

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