Intratracheal and oral administration of SM-276001: a selective TLR7 agonist, leads to antitumor efficacy in primary and metastatic models of cancer.
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.
Pharmacology Research Laboratories, Drug Research Division, Dainippon Sumitomo Pharma, 3-1-98, Kasugade Naka, Konohana-ku, Osaka, Japan. Erina-koga@ds-pharma.co.jp
Erina
E
Koga-Yamakawa
Simon J
SJ
Dovedi
Masashi
M
Murata
Hiroyuki
H
Matsui
Andrew J
AJ
Leishman
John
J
Bell
Douglas
D
Ferguson
Simon P
SP
Heaton
Toshihiro
T
Oki
Hideyuki
H
Tomizawa
Ash
A
Bahl
Haruo
H
Takaku
Robert W
RW
Wilkinson
Hideyuki
H
Harada
D000284:Administration, Oral; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects; D045744:Cell Line, Tumor; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical; D005260:Female; D016898:Interferon-alpha / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D037181:Lectins, C-Type / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000378:metabolism; D014132:Trachea; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D018925:Chemokines; D016207:Cytokines; D016898:Interferon-alpha; D053762:Interleukin-12 Subunit p40; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens; C477038:Tlr7 protein, mouse