| 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
|
| リソース情報 |
| ヒト・動物細胞 |
10T1/2(RCB0247)
293T(RCB2202) |
