The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF-4878691)

Fidock,; Be, Souberbielle; Laxton, Carl; Rawal, Jaiessh; Delpuech-Adams, Oona E; Corey, TP; Colman, Peter; Kumar, Vinay; Cheng, J B; Wright, Katherine; Srinivasan, Subasree; Rana, Khurram; Craig, Charles; Horscroft, Nigel; Perros, Manos; Westby, Michael; Webster, Robert O.; Ryst, Elna van der

doi:10.1038/clpt.2011.60

Cited by 69 publications

(61 citation statements)

References 33 publications

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“…administration of SD-101 generated adaptive antitumor immunity (30). Recent reports indicate a few safety concerns after the systemic administration of TLR agonists (42), including lymphopenia and flu-like symptoms (65). A repeated systemic administration of TLR agonists can also induce a state of immune unresponsiveness, known as TLR tolerance (Supplemental Figure 10B) (66).…”

Section: Discussionmentioning

confidence: 99%

Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer

Sato-Kaneko¹,

Yao²,

Ahmadi³

et al. 2017

JCI Insight

233

180

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Section: Discussionmentioning

confidence: 99%

Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer

Sato-Kaneko¹,

Yao²,

Ahmadi³

et al. 2017

JCI Insight

233

180

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“…These data strongly support the concept of developing a TLR7 agonist to treat allergic disease, although current TLR7 agonists, used clinically in nonallergic indications, have side effects. These include influenza-like symptoms and lymphopenia and are linked to levels of compound in the plasma and the associated cytokine induction (19)(20)(21).…”

mentioning

confidence: 99%

TLR7 Stimulation of APCs Results in Inhibition of IL-5 through Type I IFN and Notch Signaling Pathways in Human Peripheral Blood Mononuclear Cells

Edwards

Jones

Leishman

et al. 2013

The Journal of Immunology

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TLR7 agonists modulate Th2 immune responses through mechanisms that have not been fully elucidated. Suppression of IL-5 production from Ag- or phytohemagglutinin-stimulated human PBMCs by the TLR7 antedrug AZ12441970 was mediated via type I IFN–dependent and type I IFN–independent mechanisms through TLR7 activation of plasmacytoid dendritic cells, B cells, and monocytes. The type I IFN–dependent inhibition of T cell–derived IL-5 was mediated by IFN-α acting directly on activated T cells. IL-10 was shown not to be involved in the type I IFN–independent inhibition of IL-5 and the mechanism of inhibition required cell–cell interaction. Notch signaling was implicated in the inhibition of IL-5, because addition of a γ-secretase inhibitor blocked the type I IFN–independent suppression of IL-5. Accordingly, AZ12441970 induced high levels of the notch ligands Dll1 and Dll4 mRNA, whereas immobilized DLL4 resulted in the suppression of IL-5 production. Therefore, we have elucidated two mechanisms whereby TLR7 agonists can modulate IL-5 production in human T cells. The suppression of Th2 cytokines, including IL-5, would be of benefit in diseases such as atopic asthma, so we assessed TLR7 function in PBMC from asthmatics and showed equivalent activity compared with healthy volunteers. Demonstrating this function is intact in asthmatics and knowing it links to suppression of Th2 cytokines support the case for developing such compounds for the treatment of allergic disease.

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“…Imiquimod, a TLR7/8 agonist, has seen extensive clinical use (3,5) as a topical chemotherapeutic and antiviral. Experimental therapies employing TLR7 agonists have also demonstrated some clinical benefit in viral hepatitis (49), however, adverse immunologic events related to widespread biodistribution were observed at therapeutic doses (50,51) including unacceptable toxicity in a human trial of oral imiquimod (52). No adverse effects were observed in mice injected with LRNPs in this study, though long-term and dose-response effects of LRNP administration need to be investigated.…”

Section: Discussionmentioning

confidence: 73%

Lipid-derived nanoparticles for immunostimulatory RNA adjuvant delivery

Nguyen

Mahon

Chikh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The specific activation of Toll-like receptors (TLRs) has potential utility for a variety of therapeutic indications including antiviral immunotherapy and as vaccine adjuvants. TLR7 and TLR 8 may be activated by their native ligands, single-stranded RNA, or by small molecules of the imidazoquinoline family. However the use of TLR7/8 agonists for in vivo therapy is limited by instability, in the case of RNA, or systemic biodistribution and toxicity in the case of small molecule agonists. We hypothesized that unique lipid-like materials, termed "lipidoids," could be designed to efficiently deliver immunostimulatory RNA (isRNA) to TLR-expressing cells to drive innate and adaptive immune responses. A library of lipidoids was synthesized and screened for the ability to induce type I IFN activation in human peripheral blood mononuclear cells when combined with isRNA oligonucleotides. Effective lipidoid-isRNA nanoparticles, when tested in mice, stimulated strong IFN-α responses following subcutaneous injection, had robust antiviral activity that suppressed influenza virus replication, and enhanced antiovalbumin humoral and cell-mediated responses when used as a vaccine adjuvant. Further, we demonstrate that whereas all immunological activity was MyD88-dependent, certain materials were found to engage both TLR7-dependent and TLR7-independent activity in the mouse suggestive of cell-specific delivery. These lipidoid formulations, which are materials designed specifically for delivery of isRNA to Toll-like receptors, were superior to the commonly used N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate-RNA delivery system and may provide new tools for the manipulation of TLR responses in vitro and in vivo.innate immunity | dendritic cell | drug delivery | high-throughput screening

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The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF-4878691)

Cited by 69 publications

References 33 publications

Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer

Combination immunotherapy with TLR agonists and checkpoint inhibitors suppresses head and neck cancer

TLR7 Stimulation of APCs Results in Inhibition of IL-5 through Type I IFN and Notch Signaling Pathways in Human Peripheral Blood Mononuclear Cells

Lipid-derived nanoparticles for immunostimulatory RNA adjuvant delivery

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