A phase I clinical trial of imiquimod, an oral interferon inducer, administered daily

Abstract

Summary Imiquimod is an orally active interferon inducer with anti-tumour activity in experimental animals. In this study the tolerability, toxicity and biological effects of daily oral imiquimod administration were investigated in 21 patients with refractory cancer. Patients were treated with doses of 25 mg, 50 mg, 100 mg or 200 mg on a projected 112 day course. Only three patients completed the course, all at the 50 mg dose.Treatment toxicities were dose related and mainly comprised flu-like symptoms, nausea and lymphopenia. Of the 21 patients, five received dose reductions and in five treatment was discontinued because of treatmentrelated toxicity. The biological activity of imiquimod was confirmed by significant and sustained rises in peripheral blood mononuclear cell (PBMC) 2-5A synthetase (2-5AS) levels at all doses. At 100 mg and 200 mg these occurred within the first 24 h of administration. Levels of neopterin and fi2-microglobulin (A32M) were also significantly elevated when assessed after three weeks' treatment. Interferon production was not demonstrated within the first 24 h of the initial dose but, following repeated doses, ten of the patients developed detectable serum interferon concentrations with a maximum value of 5600 IU ml recorded. Administration of imiquimod did not have any significant effect on serum levels of tumour necrosis factor (TNF) or interleukin 1 (IL-1), nor did it lead to development of detectable levels of antibodies to interferon.One mixed clinical response was observed after 4 weeks' treatment at 100 mg in a patient with renal cell cancer. Daily administration of imiquimod causes activation of the interferon production system but at higher doses results in unacceptable toxicity. Further investigation of imiquimod as an interferon-inducing agent in cancer patients is suggested at either the lower dose levels or employing alternative dosing schedules.

An Exploratory Study of Systemic Administration of the Toll-like Receptor-7 Agonist 852A in Patients with Refractory Metastatic Melanoma

“…Although f1/3 of patients had adverse events of severe intensity, and doselimiting toxicities occurred at 0.6 and 0.9 mg/m 2 , the overall safety profile was deemed tolerable, given the underlying disease. Although limited by the patient number and historical comparison, the gastrointestinal adverse events observed in this study seemed to be less frequent and/or less severe than observed in clinical studies of oral administration of imiquimod or resiquimod (19,20). The intestinal tract contains a large number of immune cells, including dendritic cells, and TLR7 expression has been reported on hepatocytes (21,22).…”

Impaired Antiviral Response and Alpha/Beta Interferon Induction in Mice Lacking Beta Interferon

“…It is known that double-stranded RNA, produced during a variety of viral infections, can induce transcription of IFN-␣/␤ genes, but nonviral inducers have also been described (4,36,41). Induction of the IFN␤ gene has been extensively studied in cell culture, leading to a detailed knowledge of cis-acting sequences and binding factors required for transcriptional induction (16); a similar but less complete analysis of IFN-␣ induction has been carried out (27).…”

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.…”