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

// Simon J. Dovedi 1, 5 , Amy L. Adlard 2 , Yosuke Ota 3 , Masashi Murata 3 , Eiji Sugaru 3 , Erina Koga-Yamakawa 3 , Ken Eguchi 3 , Yuko Hirose 3 , Setsuko Yamamoto 3 , Hiroki Umehara 3 , Jamie Honeychurch 1 , Eleanor J. Cheadle 1 , Gareth Hughes 4 , Philip J. Jewsbury 4 , Robert W. Wilkinson 4, 5, * , Ian J. Stratford 2, * , Timothy M. Illidge 1, * 1 Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK 2 Manchester Pharmacy School, Manchester Cancer Research Centre, University of Manchester, Manchester, UK 3 Sumitomo Dainippon Pharma, Konohana-ku, Osaka, Japan 4 AstraZeneca Pharmaceuticals Ltd., Alderley Park, Cheshire, UK 5 Current address: MedImmune Ltd., Granta Park, Cambridge, UK * These authors contributed equally to this work Correspondence to: Simon J. Dovedi, e-mail: Simon.Dovedi@ics.manchester.ac.uk , DovediSi@MedImmune.com Keywords: TLR7, immunotherapy, radiotherapy, radiation, toll-like receptor Received: September 14, 2015      Accepted: February 05, 2016      Published: March 05, 2016 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.