論文 - 詳細
| RRC ID | 71976 |
|---|---|
| 著者 | Ishii M, Ando J, Yamazaki S, Toyota T, Ohara K, Furukawa Y, Suehara Y, Nakanishi M, Nakashima K, Ohshima K, Nakauchi H, Ando M. |
| タイトル | iPSC-Derived Neoantigen-Specific CTL Therapy for Ewing Sarcoma. |
| ジャーナル | Cancer Immunol Res |
| Abstract |
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. |
| 巻・号 | 9(10) |
| ページ | 1175-1186 |
| 公開日 | 2021-10-1 |
| DOI | 10.1158/2326-6066.CIR-21-0193 |
| PII | 2326-6066.CIR-21-0193 |
| PMID | 34385178 |
| MeSH | Animals Cell Line, Tumor Cell Proliferation* Cell- and Tissue-Based Therapy* Female Gene Expression Regulation, Neoplastic Humans Induced Pluripotent Stem Cells / metabolism* Mice Oncogene Proteins, Fusion / genetics Proto-Oncogene Protein c-fli-1 / genetics RNA-Binding Protein EWS / genetics Sarcoma, Ewing / genetics Sarcoma, Ewing / pathology Sarcoma, Ewing / therapy* Xenograft Model Antitumor Assays |
| IF | 8.728 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 6 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | 10T1/2(RCB0247) 293T(RCB2202) |