論文 - 詳細
| RRC ID | 65457 |
|---|---|
| 著者 | Goto S, Sakoda Y, Adachi K, Sekido Y, Yano S, Eto M, Tamada K. |
| タイトル | Enhanced anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells in orthotopic and patient-derived xenograft tumor models. |
| ジャーナル | Cancer Immunol Immunother |
| Abstract |
Chimeric antigen receptor (CAR)-T cell therapy has impressive efficacy in hematological malignancies, but its application in solid tumors remains a challenge. Multiple hurdles associated with the biological and immunological features of solid tumors currently limit the application of CAR-T cells in the treatment of solid tumors. Using syngeneic mouse models, we recently reported that CAR-T cells engineered to concomitantly produce interleukin (IL)-7 and chemokine (C-C motif) ligand 19 (CCL19)-induced potent anti-tumor efficacy against solid tumors through an improved ability of migration and proliferation even in an immunosuppressive tumor microenvironment. In this study, for a preclinical evaluation preceding clinical application, we further explored the potential of IL-7/CCL19-producing human CAR-T cells using models that mimic the clinical features of solid tumors. Human anti-mesothelin CAR-T cells producing human IL-7/CCL19 achieved complete eradication of orthotopic pre-established malignant mesothelioma and prevented a relapse of tumors with downregulated antigen expression. Moreover, mice with patient-derived xenograft of mesothelin-positive pancreatic cancers exhibited significant inhibition of tumor growth and prolonged survival following treatment with IL-7/CCL19-producing CAR-T cells, compared to treatment with conventional CAR-T cells. Transfer of IL-7/CCL19-producing CAR-T cells resulted in an increase in not only CAR-T cells but also non-CAR-T cells within the tumor tissues and downregulated the expression of exhaustion markers, including PD-1 and TIGIT, on the T cells. Taken together, our current study elucidated the exceptional anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells and their potential for clinical application in the treatment of patients with solid tumors. |
| 巻・号 | 70(9) |
| ページ | 2503-2515 |
| 公開日 | 2021-9-1 |
| DOI | 10.1007/s00262-021-02853-3 |
| PII | 10.1007/s00262-021-02853-3 |
| PMID | 33559069 |
| MeSH | Animals Cell Line, Tumor Chemokine CCL19 / genetics Chemokine CCL19 / metabolism* Disease Models, Animal Female Humans Immunophenotyping Immunotherapy, Adoptive* / methods Interleukin-7 / genetics Interleukin-7 / metabolism* Mesothelin Mesothelioma, Malignant / etiology Mesothelioma, Malignant / pathology Mesothelioma, Malignant / therapy Mice Mice, Knockout Receptors, Chimeric Antigen Recurrence T-Lymphocytes / immunology* T-Lymphocytes / metabolism* T-Lymphocytes / pathology Treatment Outcome Xenograft Model Antitumor Assays |
| IF | 5.442 |
| 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 | 7 |
| 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 | OV2944-HM-1(RCB1483) |