Therapy with TLR7 Agonists Induces Lymphopenia: Correlating Pharmacology to Mechanism in a Mouse Model

Perkins, Hannah; Khodai, Tansi; Mechiche, Houria; Colman, Peter; Burden, Frances; Laxton, Carl; Horscroft, Nigel; Corey, T.; Rodrigues, Débora F.; Rawal, Jaiessh; Heyen, Jonathan R.; Fidock, Mark; Westby, Mike; Bright, Helen

doi:10.1007/s10875-012-9687-y

Cited by 22 publications

(16 citation statements)

References 29 publications

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“…In addition, at the 5 and 10 mg/kg, GS-9620 induced transient hematological changes, including reversible decreases in platelets (26% and 75% decrease at 5 and 10 mg/kg, respectively) and lymphocytes (72% decrease at 10 mg/kg). Transient lymphocyte changes were consistent with trafficking and/or margination associated with TLR7 induced chemokines [19, 20]. Based on these single dose assessments, 5 mg/kg was chosen for the efficacy study.…”

Section: Resultsmentioning

confidence: 99%

Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B

Menne

Tumas

Liu

et al. 2015

Journal of Hepatology

191

160

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Background & Aims New therapies for chronic hepatitis B (CHB) are urgently needed since current treatments rarely lead to cure. We evaluated whether the oral small molecule toll-like receptor (TLR7) agonist GS-9620 could induce durable anti-viral efficacy in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to human hepatitis B virus (HBV). Methods After evaluating the pharmacokinetics, pharmacodynamics and tolerability of oral GS-9620 in uninfected woodchucks, adult woodchucks chronically infected with WHV (n=7 per group) were dosed with GS-9620 or placebo for 4 or 8 weeks with different treatment schedules. Results GS-9620 treatment induced rapid, marked and sustained reduction in serum viral DNA (mean maximal 6.2 log10 reduction), and hepatic WHV DNA replicative intermediates, WHV cccDNA and WHV RNA, as well as loss of detectable serum WHV surface antigen (WHsAg). GS-9620 treatment also induced a sustained antibody response against WHsAg in a subset of animals. Strikingly, treatment reduced the incidence of hepatocellular carcinoma (HCC) from 71% in the placebo group to 8% in GS-9620-treated woodchucks with sustained viral load reduction. GS-9620 treatment was associated with reversible increases in serum liver enzymes and thrombocytopenia, and induced intrahepatic CD8+ T cell, NK cell, B cell and interferon (IFN) response transcriptional signatures. Conclusions The data demonstrate that short duration, finite treatment with the oral TLR7 agonist GS-9620 can induce a sustained antiviral response in the woodchuck model of CHB, and support investigation of this compound as a therapeutic approach to attain a functional cure in CHB patients.

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Section: Resultsmentioning

confidence: 99%

Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B

Menne

Tumas

Liu

et al. 2015

Journal of Hepatology

191

160

View full text Add to dashboard Cite

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“…TLRs including TLR7 initialize the signaling pathways that primary innate responses follow in the adaptive immune system39. Based on this crucial role in the induction of a strong anti-pathogen response, TLR7 was regarded as an attractive target for anti-viral therapy with TLR7 agonists40. These TLR7 agonists can be used in the liver to treat hepatitis C. TLR7 agonists such as resiquimod, isatoribine, and ANA975 ameliorated hepatitis C virus infection by inhibiting viral attachment and inducing the immune response4142.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease

Kim

Park

Kim

et al. 2016

Sci Rep

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Recently, a possible link between toll-like receptor 7 (TLR7) and liver disease was suggested, although it was limited to fibrosis. Based on this report, we investigated whether TLR7 has a pivotal role in non-alcoholic fatty liver disease (NAFLD). The TLR7 signaling pathway, which is activated by imiquimod (TLR7 ligand) naturally, induced autophagy and released insulin-like growth factor 1 (IGF-1) into medium from hepatocytes. Lipid accumulation induced by unsaturated fatty acid (UFA; arachidonic acid:oleic acid = 1:1) in hepatocytes, was attenuated in TLR7 and autophagy activation. Interestingly, TLR7 activation attenuated UFA-induced lipid peroxidation products, such as malondialdehyde (MDA) and 4-Hydroxy-2-Nonenal (4-HNE). To clarify a possible pathway between TLR7 and lipid peroxidation, we treated hepatocytes with MDA and 4-HNE. MDA and 4-HNE induced 2-folds lipid accumulation in UFA-treated hepatocytes via blockade of the TLR7 signaling pathway’s IGF-1 release compared to only UFA-treated hepatocytes. In vivo experiments carried out with TLR7 knockout mice produced results consistent with in vitro experiments. In conclusion, TLR7 prevents progression of NAFLD via induced autophagy and released IGF-1 from liver. These findings suggest a new therapeutic strategy for the treatment of NAFLD.

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“…Although, to our knowledge, resiquimod is not being investigated in clinical trials, several studies have been performed in melanoma patients with topical administration or local injection, mainly in combination with vaccine therapy. Despite some promising results, the systemic administration of imidazoquinolines is burdened with toxicity: whole-body inflammation, hematologic toxicity (lymphopenia, anemia), and flu-like symptoms [121,122]. To solve this problem, R848 has been covalently linked to vitamin E and modified with hyaluronic acid, thus becoming a pro-drug nanoformulation.…”

Section: Targeting the Toll-like Receptors For Tam Reprogrammingmentioning

confidence: 99%

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

Anfray

Ummarino

Andón

et al. 2019

Cells

240

205

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: Established evidence demonstrates that tumor-infiltrating myeloid cells promote rather than stop-cancer progression. Tumor-associated macrophages (TAMs) are abundantly present at tumor sites, and here they support cancer proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Their pro-tumor activities hamper the response of cancer patients to conventional therapies, such as chemotherapy or radiotherapy, and also to immunotherapies based on checkpoint inhibition. Active research frontlines of the last years have investigated novel therapeutic strategies aimed at depleting TAMs and/or at reprogramming their tumor-promoting effects, with the goal of re-establishing a favorable immunological anti-tumor response within the tumor tissue. In recent years, numerous clinical trials have included pharmacological strategies to target TAMs alone or in combination with other therapies. This review summarizes the past and current knowledge available on experimental tumor models and human clinical studies targeting TAMs for cancer treatment.

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Therapy with TLR7 Agonists Induces Lymphopenia: Correlating Pharmacology to Mechanism in a Mouse Model

Cited by 22 publications

References 29 publications

Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B

Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B

Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

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