| 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
|
| リソース情報 |
| ヒト・動物細胞 |
LM8(RCB1450) |
