iPSC-Derived Neoantigen-Specific CTL Therapy for Ewing Sarcoma
iPSC-Derived Neoantigen-Specific CTL Therapy for Ewing Sarcoma
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DOI：
10.1158/2326-6066.cir-21-0193
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发表时间：
2021-10-01
影响因子：
10.1
通讯作者：
Ando, Miki
中科院分区：
文献类型：
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作者：
Ishii, Midori;Ando, Jun;Ando, Miki
EWS/FLI 1融合引起的尤文肉瘤预后差，尤其是转移后。尽管使用靶向基因断裂/融合位点处的改变的EWS/FLI 1序列的CTL的治疗可能是有效的，但是由于持续暴露于肿瘤抗原，从外周血产生的CTL通常被耗尽。我们通过产生诱导多能干细胞（iPSC）衍生的功能性再生CTL（rejT）来解决这一问题，所述CTL针对由EWS/FLI 1融合基因编码的新抗原。在这项研究中，我们研究了EWS/FLI 1-rejTs对尤文肉瘤的抗肿瘤作用。EWS/FLI 1断裂/融合点处的改变的氨基酸序列，当作为新抗原呈递时，引起靶向EWS/FLI 1（+）肉瘤的免疫应答。虽然产生的EWS/FLI 1特异性CTL的频率仅为0.003%，但我们成功地从健康供体建立了CTL克隆。我们从EWS/FLI 1特异性CTL克隆建立了iPSC，并将其再分化为EWS/FLI 1特异性rejTs。为了评估细胞毒性，我们将EWS/FLI 1-rejTs与尤文肉瘤细胞系共培养。EWS/FLI 1-rejTs快速并持续抑制尤文肉瘤的增殖> 40小时。使用尤文肉瘤异种移植小鼠模型，我们通过成像验证了EWS/FLI 1-rejTs的抗肿瘤作用，EWS/FLI 1-rejTs赋予了统计学显著的生存优势。“现成的”治疗比化疗的破坏性和破坏性小，放射治疗总是可取的，特别是在青少年中，尤因肉瘤最常见。因此，靶向尤文肉瘤新抗原的EWS/FLI 1-rejTs可能是一种有前途的新治疗工具。
The prognosis of Ewing sarcoma caused by EWS/FLI1 fusion is poor, especially after metastasis. Although therapy with CTLs targeted against altered EWS/FLI1 sequences at the gene break/fusion site may be effective, CTLs generated from peripheral blood are often exhausted because of continuous exposure to tumor antigens. We addressed this by generating induced pluripotent stem cell (iPSC)-derived functionally rejuvenated CTLs (rejT) directed against the neoantigen encoded by the EWS/FLI1 fusion gene. In this study, we examined the antitumor effects of EWS/FLI1-rejTs against Ewing sarcoma. The altered amino acid sequence at the break/fusion point of EWS/FLI1, when presented as a neoantigen, evokes an immune response that targets EWS/FLI1(+) sarcoma. Although the frequency of generated EWS/FLI1-specific CTLs was only 0.003%, we successfully established CTL clones from a healthy donor. We established iPSCs from a EWS/FLI1-specific CTL clone and redifferentiated them into EWS/FLI1-specific rejTs. To evaluate cytotoxicity, we cocultured EWS/FLI1-rejTs with Ewing sarcoma cell lines. EWS/FLI1-rejTs rapidly and continuously suppressed the proliferation of Ewing sarcoma for > 40 hours. Using a Ewing sarcoma xenograft mouse model, we verified the antitumor effect of EWS/FLI1-rejTs via imaging, and EWS/FLI1-rejTs conferred a statistically significant survival advantage. "Off-the-shelf" therapy is less destructive and disruptive than chemotherapy, and radiation is always desirable, particularly in adolescents, whom Ewing sarcoma most often affects. Thus, EWS/FLI1-rejTs targeting a Ewing sarcoma neoantigen could be a promising new therapeutic tool.