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Intratracheal and oral administration of SM‐276001: A selective TLR7 agonist, leads to antitumor efficacy in primary and metastatic models of cancer
Author(s) -
KogaYamakawa Erina,
Dovedi Simon J.,
Murata Masashi,
Matsui Hiroyuki,
Leishman Andrew J.,
Bell John,
Ferguson Douglas,
Heaton Simon P.,
Oki Toshihiro,
Tomizawa Hideyuki,
Bahl Ash,
Takaku Haruo,
Wilkinson Robert W.,
Harada Hideyuki
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27691
Subject(s) - medicine , agonist , imiquimod , metastasis , adjuvant , cancer , immune system , oral administration , cytokine , chemokine , tlr7 , pharmacology , immunology , cancer research , receptor , innate immune system , toll like receptor
Topical TLR7 agonists such as imiquimod are highly effective for the treatment of dermatological malignancies; however, their efficacy in the treatment of nondermatological tumors has been less successful. We report that oral administration of the novel TLR7‐selective small molecule agonist; SM‐276001, leads to the induction of an inflammatory cytokine and chemokine milieu and to the activation of a diverse population of immune effector cells including T and B lymphocytes, NK and NKT cells. Oral administration of SM‐276001 leads to the induction of IFNα, TNFα and IL‐12p40 and a reduction in tumor burden in the Balb/c syngeneic Renca and CT26 models. Using the OV2944‐HM‐1 model of ovarian cancer which spontaneously metastasizes to the lungs following subcutaneous implantation, we evaluated the efficacy of intratracheal and oral administration of SM‐276001 in an adjuvant setting following surgical resection of the primary tumor. We show that both oral and intratracheal TLR7 therapy can reduce the frequency of pulmonary metastasis, and metastasis to the axillary lymph nodes. These results demonstrate that SM‐276001 is a potent selective TLR7 agonist that can induce antitumor immune responses when dosed either intratracheally or orally.