A novel systemically administered toll‐like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models

• Published in: International journal of cancer Vol. 135; no. 4; pp. 820 - 829
• Main Authors: Adlard, Amy L., Dovedi, Simon J., Telfer, Brian A., Koga‐Yamakawa, Erina, Pollard, Charlotte, Honeychurch, Jamie, Illidge, Timothy M., Murata, Masashi, Robinson, David T., Jewsbury, Philip J., Wilkinson, Robert W., Stratford, Ian J.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 15.08.2014; Wiley Subscription Services, Inc; BlackWell Publishing Ltd
• Subjects: Adenine - administration & dosage; Adenine - analogs & derivatives; Animals; B-Lymphocytes - drug effects; B-Lymphocytes - radiation effects; Biological and medical sciences; Cancer; Chemotherapy; combination therapy; Disease Models, Animal; Drug delivery systems; Female; HEK293 Cells; Humans; immunotherapy; Immunotherapy - methods; Interferon-gamma - metabolism; Killer Cells, Natural - drug effects; Killer Cells, Natural - radiation effects; Lung - pathology; Medical research; Medical sciences; Membrane Glycoproteins - agonists; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Knockout; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); murine tumor model; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms - radiotherapy; Radiation therapy; Radiation, Ionizing; radiotherapy; Spleen - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - radiation effects; TLR7; Toll-Like Receptor 7 - agonists; Tumor Immunology; Tumors; Toll like receptor 7; Animal model; Solid tumor; Agonist; Drug combination; Rodentia; Malignant tumor; Radiotherapy; Vertebrata; Ionizing radiation; Mammalia; Cancerology; Mouse; Immunotherapy; combination therapy; Combined treatment; TLR7; murine tumor model; Cancer; radiotherapy; immunotherapy
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28711

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. What's new? Recent evidence suggests that damage from ionizing radiation (IR) can render tumor cells immunogenic. Unfortunately, established tumors often suppress this anti‐tumor immune response. Combination therapy with IR and immune‐modulators such as Toll‐like‐receptor (TLR) family agonists may overcome this problem. In this proof‐of‐concept study, the authors examined one such small‐molecule drug, called DSR‐6434. They found that systemic administration of DSR‐6434 can enhance the effectiveness of radiotherapy in mice, and that this occurs via the generation of tumor‐specific immune responses. Easily delivered drugs that activate TLR‐family molecules may thus offer a promising therapeutic approach.