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A novel systemically administered Toll-like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models.
- Source :
-
International journal of cancer [Int J Cancer] 2014 Aug 15; Vol. 135 (4), pp. 820-9. Date of Electronic Publication: 2014 Jan 17. - Publication Year :
- 2014
-
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.<br /> (© 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.)
- Subjects :
- Adenine administration & dosage
Animals
B-Lymphocytes drug effects
B-Lymphocytes radiation effects
Disease Models, Animal
Female
HEK293 Cells
Humans
Interferon-gamma metabolism
Killer Cells, Natural drug effects
Killer Cells, Natural radiation effects
Lung pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
Mice, Knockout
Neoplasm Metastasis
Neoplasm Transplantation
Radiation, Ionizing
Spleen cytology
T-Lymphocytes drug effects
T-Lymphocytes radiation effects
Adenine analogs & derivatives
Immunotherapy methods
Membrane Glycoproteins agonists
Neoplasms radiotherapy
Toll-Like Receptor 7 agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0215
- Volume :
- 135
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 24390981
- Full Text :
- https://doi.org/10.1002/ijc.28711