title: 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.
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.
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.|Current address: MedImmune Ltd., Granta Park, Cambridge, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dovedi
authors.affiliation: Manchester Pharmacy School, Manchester Cancer Research Centre, University of Manchester, Manchester, UK.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Adlard
authors.affiliation: Sumitomo Dainippon Pharma, Konohana-ku, Osaka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ota
authors.affiliation: Sumitomo Dainippon Pharma, Konohana-ku, Osaka, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Murata
authors.affiliation: Sumitomo Dainippon Pharma, Konohana-ku, Osaka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugaru
authors.affiliation: Sumitomo Dainippon Pharma, Konohana-ku, Osaka, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Koga-Yamakawa
authors.affiliation: Sumitomo Dainippon Pharma, Konohana-ku, Osaka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Eguchi
authors.affiliation: Sumitomo Dainippon Pharma, Konohana-ku, Osaka, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hirose
authors.affiliation: Sumitomo Dainippon Pharma, Konohana-ku, Osaka, Japan.
authors.forename: Setsuko
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Sumitomo Dainippon Pharma, Konohana-ku, Osaka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Umehara
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Honeychurch
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Cheadle
authors.affiliation: AstraZeneca Pharmaceuticals Ltd., Alderley Park, Cheshire, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Hughes
authors.affiliation: AstraZeneca Pharmaceuticals Ltd., Alderley Park, Cheshire, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Jewsbury
authors.affiliation: AstraZeneca Pharmaceuticals Ltd., Alderley Park, Cheshire, UK.|Current address: MedImmune Ltd., Granta Park, Cambridge, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.affiliation: Manchester Pharmacy School, Manchester Cancer Research Centre, University of Manchester, Manchester, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Illidge
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D059248:Chemoradiotherapy / Q000379:methods*; D019583:Dose Fractionation, Radiation; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: D000970:Antineoplastic Agents; C000625326:DSR-29133; D051199:Toll-Like Receptor 7; D000225:Adenine
keywords: TLR7; immunotherapy; radiation; radiotherapy; toll-like receptor