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
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Simon J. Dovedi1,5, Amy L. Adlard2, Yosuke Ota3, Masashi Murata3, Eiji Sugaru3, Erina Koga-Yamakawa3, Ken Eguchi3, Yuko Hirose3, Setsuko Yamamoto3, Hiroki Umehara3, Jamie Honeychurch1, Eleanor J. Cheadle1, Gareth Hughes4, Philip J. Jewsbury4, Robert W. Wilkinson4,5,*, Ian J. Stratford2,*, Timothy M. Illidge1,*
1Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
2Manchester Pharmacy School, Manchester Cancer Research Centre, University of Manchester, Manchester, UK
3Sumitomo Dainippon Pharma, Konohana-ku, Osaka, Japan
4AstraZeneca Pharmaceuticals Ltd., Alderley Park, Cheshire, UK
5Current address: MedImmune Ltd., Granta Park, Cambridge, UK
*These authors contributed equally to this work
Keywords: TLR7, immunotherapy, radiotherapy, radiation, toll-like receptor
Received: September 14, 2015 Accepted: February 05, 2016 Published: March 05, 2016
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.
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