IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas.
IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas.
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DOI：
10.1371/journal.pone.0133152
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhou X
中科院分区：
文献类型：
--
作者：
Huang X;Park H;Greene J;Pao J;Mulvey E;Zhou SX;Albert CM;Moy F;Sachdev D;Yee D;Rader C;Hamby CV;Loeb DM;Cairo MS;Zhou X
转移性或复发性难治性肉瘤的患者预后很差。因此，迫切需要新的靶向治疗。本研究旨在评估针对I型胰岛素样生长因子受体(IGF1R)或酪氨酸激酶样孤儿受体1(ROR1)分子的嵌合抗原受体(CAR)T细胞对肉瘤的治疗潜力。在此，我们报道了IGF1R(15/15)和ROR1(11/15)在尤文肉瘤、骨肉瘤、肺泡型或胚胎型横纹肌肉瘤和纤维肉瘤等肉瘤细胞系中高表达。使用睡美人转座子系统从8名健康捐赠者获得的IGF1R和ROR1CAR T细胞对肉瘤细胞具有细胞毒作用，并以抗原特异性的方式产生高水平的干扰素-γ、肿瘤坏死因子-α和IL-13。来自三名肉瘤患者的IGF1R和ROR1CAR T细胞在肉瘤刺激下释放大量的干扰素-γ。过继转移来自肉瘤患者的IGF1R和ROR1CAR T细胞显著减少了NSG小鼠预先建立的、系统播散的和局部的骨肉瘤异种移植模型中的肿瘤生长。在使用NOD/SCID小鼠的局部肉瘤模型中，输注IGF1R和ROR1CAR细胞也延长了动物的存活时间。我们的数据表明，IGF1R和ROR1都可以有效地被SB修饰的CAR T细胞靶向，这种CAR T细胞可能在高危肉瘤患者的治疗中有用。
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 the Sleeping Beauty (SB) transposon system were cytotoxic against sarcoma cells and produced high levels of IFN-γ, TNF-α and IL-13 in an antigen-specific manner. IGF1R and ROR1 CAR T cells generated from three sarcoma patients released significant amounts of IFN-γ in 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.