Intratracheal and oral administration of SM‐276001: A selective TLR7 agonist, leads to antitumor efficacy in primary and metastatic models of cancer

Koga-Yamakawa, Erina; Dovedi, Simon J.; Murata, Masashi; Matsui, Hiroyuki; Leishman, Andrew J.; Bell, John P.; Ferguson, Douglas; Heaton, Simon P.; Oki, Toshihiro; Tomizawa, Hideyuki; Bahl, Ash; Takaku, Haruo; Wilkinson, Robert W.; Harada, Hideyuki

doi:10.1002/ijc.27691

Cited by 27 publications

(23 citation statements)

References 36 publications

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“…In this study, we implicate involvement of a group of upstream regulators related to the immune system that are actually activated in the aged host and are documented in the literature to inhibit or slow tumor progression. This group includes TLR2 (28), TLR7 (29), IL12 (30) and CD247 (31). When activated, Toll-like receptor 2 (TLR2) has even been reported to induce tumor regression (28).…”

Section: Discussionmentioning

confidence: 99%

Proton Irradiation Augments the Suppression of Tumor Progression Observed with Advanced Age

et al. 2014

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Proton radiation is touted for improved tumor targeting, over standard gamma radiation, due to the physical advantages of ion beams for radiotherapy. Recent studies from our laboratory demonstrate that in addition to these targeting advantages, proton irradiation can inhibit angiogenic and immune factors critical to “hallmark” processes that impact cancer progression, thereby modulating tumor development. Outside the therapeutic utilization of protons, high-energy protons constitute a principal component of galactic cosmic rays and thus are a consideration in carcinogenesis risk for space flight. Given that proton irradiation modulates fundamental biological processes known to decrease with aging (e.g. angiogenesis and immunogenicity), we investigated how proton irradiation impacts tumor advancement as a function of host age, a question with both therapeutic and carcinogenesis implications. Tumor lag time and growth dynamics were tracked, after injection of murine Lewis lung carcinoma (LLC) cells into syngeneic adolescent (68 day) vs. old (736 day) C57BL/6 mice with or without coincident irradiation. Tumor growth was suppressed in old compared to adolescent mice. These differences were further modulated by proton irradiation (1 GeV), with increased inhibition and a significant radiation-altered molecular fingerprint evident in tumors grown in old mice. Through global transcriptome analysis, TGFβ1 and TGFβ2 were determined to be key players that contributed to the tumor dynamics observed. These findings suggest that old hosts exhibit a reduced capacity to support tumor advancement, which can be further reduced by proton irradiation.

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Section: Discussionmentioning

confidence: 99%

Proton Irradiation Augments the Suppression of Tumor Progression Observed with Advanced Age

et al. 2014

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“…The novel TLR7 agonist SZU-101 which was synthesized in ShenZhen University was also applied to immune adjuvant and acquired prospective outcomes (Wang et al, 2015; Diao et al, 2016). There are also many TLR7 agonists attracting researchers' interest: SM-276001 and SM -360320 are selective TLR7 agonist, and SM-360320 can synergize with DNA vaccines targeting CEA colon cancer and HER2 breast cancer (Dharmapuri et al, 2009; Koga-Yamakawa et al, 2013). …”

Section: Other Agonistsmentioning

confidence: 99%

Anti-tumor Activity of Toll-Like Receptor 7 Agonists

et al. 2017

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Toll-like receptors (TLRs) are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity. The activated TLRs not only induce inflammatory responses, but also elicit the development of antigen specific immunity. TLR7, a member of TLR family, is an intracellular receptor expressed on the membrane of endosomes. TLR7 can be triggered not only by ssRNA during viral infections, but also by immune modifiers that share a similar structure to nucleosides. Its powerful immune stimulatory action can be potentially used in the anti-tumor therapy. This article reviewed the anti-tumor activity and mechanism of TLR7 agonists that are frequently applied in preclinical and clinical investigations, and mainly focused on small synthetic molecules, including imiquimod, resiquimod, gardiquimod, and 852A, etc.

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“…More recently, the development of novel small molecule toll-like receptor (TLR)7-selective agonists has permitted the activation of distinct immune effector cells with a greater capacity than broadadjuvant-based approaches to polarize immune responses [1,2]. Whilst topical TLR7 agonists such as imiquimod have proven effective for the treatment of dermatologic malignancy, systemically tolerated TLR7 agonists may be required for the treatment of the majority of solid cancers.…”

Section: Introductionmentioning

confidence: 99%

TLR7 tolerance is independent of the type I IFN pathway and leads to loss of anti-tumor efficacy in mice

Koga-Yamakawa

Murata

Dovedi

et al. 2015

Cancer Immunol Immunother

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Systemic administration of small molecule toll-like receptor (TLR)-7 agonists leads to potent activation of innate immunity and to the generation of anti-tumor immune responses. However, activation of TLRs with small molecule agonists may lead to the induction of TLR tolerance, defined as a state of hyporesponsiveness to subsequent agonism, which may limit immune activation, the generation of anti-tumor responses and clinical response. Our data reveal that dose scheduling impacts on the efficacy of systemic therapy with the selective TLR7 agonist, 6-amino-2-(butylamino)-9-((6-(2-(dimethylamino)ethoxy)pyridin-3-yl)methyl)-7,9-dihydro-8H-purin-8-one (DSR-6434). In a preclinical model of renal cell cancer, systemic administration of DSR-6434 dosed once weekly resulted in a significant anti-tumor response. However, twice weekly dosing of DSR-6434 led to the induction of TLR tolerance, and no anti-tumor response was observed. We show that TLR7 tolerance was independent of type I interferon (IFN) negative feedback because induction of TLR7 tolerance was also observed in IFN-α/β receptor knockout mice treated with DSR-6434. Moreover, our data demonstrate that treatment of bone marrow-derived plasmacytoid dendritic cells (BM-pDC) with DSR-6434 led to downregulation of TLR7 expression. From our data, dose scheduling of systemically administered TLR7 agonists can impact on anti-tumor activity through the induction of TLR tolerance. Furthermore, TLR7 expression on pDC may be a useful biomarker of TLR7 tolerance and aid in the optimization of dosing schedules involving systemically administered TLR7 agonists.

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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

Cited by 27 publications

References 36 publications

Proton Irradiation Augments the Suppression of Tumor Progression Observed with Advanced Age

Proton Irradiation Augments the Suppression of Tumor Progression Observed with Advanced Age

Anti-tumor Activity of Toll-Like Receptor 7 Agonists

TLR7 tolerance is independent of the type I IFN pathway and leads to loss of anti-tumor efficacy in mice

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