論文 - 詳細
| RRC ID | 62778 |
|---|---|
| 著者 | Dovedi SJ, Adlard AL, Ota Y, Murata M, Sugaru E, Koga-Yamakawa E, Eguchi K, Hirose Y, Yamamoto S, Umehara H, Honeychurch J, Cheadle EJ, Hughes G, Jewsbury PJ, Wilkinson RW, Stratford IJ, Illidge TM. |
| タイトル | Intravenous administration of the selective toll-like receptor 7 agonist DSR-29133 leads to anti-tumor efficacy in murine solid tumor models which can be potentiated by combination with fractionated radiotherapy. |
| ジャーナル | Oncotarget |
| Abstract |
Strategies to augment anti-cancer immune responses have recently demonstrated therapeutic utility. To date clinical success has been achieved through targeting co-inhibitory checkpoints such as CTLA-4, PD-1, and PD-L1. However, approaches that target co-activatory pathways are also being actively being developed. Here we report that the novel TLR7-selective agonist DSR-29133 is well tolerated in mice and leads to acute immune activation. Administration of DSR-29133 leads to the induction of IFNα/γ, IP-10, TNFα, IL-1Ra and IL-12p70, and to a reduction in tumor burden in syngeneic models of renal cancer (Renca), metastatic osteosarcoma (LM8) and colorectal cancer (CT26). Moreover, we show that the efficacy of DSR-29133 was significantly improved when administered in combination with low-dose fractionated radiotherapy (RT). Effective combination therapy required weekly administration of DSR-29133 commencing on day 1 of a fractionated RT treatment cycle, whereas no enhancement of radiation response was observed when DSR-29133 was administered at the end of the fractionated RT cycle. Combined therapy resulted in curative responses in a high proportion of mice bearing established CT26 tumors which was dependent on the activity of CD8+ T-cells but independent of CD4+ T-cells and NK/NKT cells. Moreover, long-term surviving mice originally treated with DSR-29133 and RT were protected by a tumor-specific memory immune response which could prevent tumor growth upon rechallenge. These results demonstrate that DSR-29133 is a potent selective TLR7 agonist that when administered intravenously can induce anti-tumor immune responses that can be further enhanced through combination with low-dose fractionated RT. |
| 巻・号 | 7(13) |
| ページ | 17035-46 |
| 公開日 | 2016-3-29 |
| DOI | 10.18632/oncotarget.7928 |
| PII | 7928 |
| PMID | 26959743 |
| PMC | PMC4941369 |
| MeSH | Adenine / analogs & derivatives* Adenine / pharmacology Administration, Intravenous Animals Antineoplastic Agents / pharmacology* CD8-Positive T-Lymphocytes / drug effects CD8-Positive T-Lymphocytes / immunology Chemoradiotherapy / methods* Dose Fractionation, Radiation Humans Lymphocyte Activation / drug effects Mice Neoplasms, Experimental / drug therapy* Neoplasms, Experimental / immunology Neoplasms, Experimental / radiotherapy Toll-Like Receptor 7 / agonists* |
| IF | 5.168 |
| 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 | 2 |
| 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 | LM8(RCB1450) |