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

Abstract

Hepatitis C virus (HCV) infection is an issue of global concern, and studies are ongoing to identify new therapies that are both effective and safe. PF-4878691 is a Toll-like receptor 7 (TLR7) agonist modeled so as to dissociate its antiviral activities from its inflammatory activities. In a proof-of-mechanism study in healthy volunteers who received doses of 3, 6, and 9 mg of PF-4878691 twice a week for 2 weeks, PF-4878691 induced biomarkers of the immune and interferon (IFN) responses in a dose-dependent and dose-frequency-related manner. A novel finding was induction of TLR7 expression in vivo in response to PF-4878691, leading to an amplified biomarker response. A nonresponder at the 9-mg dose had a polymorphism in the IFN-α receptor 1 subunit (Val168Leu). Two subjects who had received 9-mg doses experienced serious adverse events (SAEs), characterized by flu-like symptoms, hypotension, and lymphopenia, leading to early termination of the study. TLR7 stimulation results in a pharmacologic response at levels commensurate with predicted antiviral efficacy, but these doses are associated with SAEs, raising concerns about the therapeutic window of this class of compounds for the treatment of HCV infection.

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

“…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).…”

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

“…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).…”

Lipid-derived nanoparticles for immunostimulatory RNA adjuvant delivery

“…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.…”