title: A novel systemically administered Toll-like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models.
abstract: Although topical TLR7 therapies such as imiquimod have proved successful in the treatment of dermatological malignancy, systemic delivery may be required for optimal immunotherapy of nondermatological tumors. We report that intravenous delivery of the novel small molecule TLR7 agonist, DSR-6434, leads to the induction of type 1 interferon and activation of T and B lymphocytes, NK and NKT cells. Our data demonstrate that systemic administration of DSR-6434 enhances the efficacy of ionizing radiation (IR) and leads to improved survival in mice bearing either CT26 or KHT tumors. Of the CT26 tumor-bearing mice that received combined therapy, 55% experienced complete tumor resolution. Our data reveal that these long-term surviving mice have a significantly greater frequency of tumor antigen specific CD8(+) T cells when compared to age-matched tumor-naïve cells. To evaluate therapeutic effects on spontaneous metastases, we showed that combination of DSR-6434 with local IR of the primary tumor significantly reduced metastatic burden in the lung, when compared to time-matched cohorts treated with IR alone. The data demonstrate that systemic administration of the novel TLR7 agonist DSR-6434 in combination with IR primes an antitumor CD8(+) T-cell response leading to improved survival in syngeneic models of colorectal carcinoma and fibrosarcoma. Importantly, efficacy extends to sites outside of the field of irradiation, reducing metastatic load. Clinical evaluation of systemic TLR7 therapy in combination with IR for the treatment of solid malignancy is warranted.
authors.affiliation: Experimental Oncology Group, School of Pharmacy and Pharmaceutical Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Adlard
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dovedi
authors.forename: Brian A
authors.initials: BA
authors.lastname: Telfer
authors.forename: Erina
authors.initials: E
authors.lastname: Koga-Yamakawa
authors.forename: Charlotte
authors.initials: C
authors.lastname: Pollard
authors.forename: Jamie
authors.initials: J
authors.lastname: Honeychurch
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Illidge
authors.forename: Masashi
authors.initials: M
authors.lastname: Murata
authors.forename: David T
authors.initials: DT
authors.lastname: Robinson
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Jewsbury
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000528:radiation effects; D008168:Lung / Q000473:pathology; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000532:radiotherapy*; D011839:Radiation, Ionizing; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: C581841:DSR-6434; D008562:Membrane Glycoproteins; C495348:TLR7 protein, human; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D007371:Interferon-gamma; D000225:Adenine
keywords: TLR7; combination therapy; immunotherapy; murine tumor model; radiotherapy