Original paperPhase II trial of intravenous endotoxin in patients with colorectal and non-small cell lung cancer
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2023, Journal of Photochemistry and Photobiology B: BiologyToll-Like Receptors
2022, Encyclopedia of Infection and ImmunitySafety, Pharmacokinetics, and Pharmacodynamics of the TLR4 Agonist GSK1795091 in Healthy Individuals: Results from a Randomized, Double-blind, Placebo-controlled, Ascending Dose Study
2020, Clinical TherapeuticsCitation Excerpt :Part 1 was planned to enroll up to 8 sequential cohorts of 8 participants per cohort (6 active and 2 placebo), with a dose escalation of 7, 21, 60, 120, 180, 280, 420, and 630 ng. The starting dose of 7 ng was selected based on the minimum anticipated biological effect level, determined in a cynomolgus monkey model, and was considered to be conservative compared with the 20- to 40-fold higher doses of LPS routinely used in healthy individuals,11,12 given that the in vitro potency of GSK1795091 is similar to (or lower than) that of LPS. On the basis of emerging clinical data from cohorts 1 to 3 and an observation of increased heart rate in the 60-ng cohort, the protocol was amended, and planned doses of GSK1795091 were revised to 7, 21, 60, 60 (repeat of previous cohort), 100, 150, and 210 ng.
Subchronic and chronic toxicity evaluation of inorganic nanoparticles for delivery applications
2019, Advanced Drug Delivery ReviewsCitation Excerpt :All drugs coming into contact with human blood are required to contain no more than 5 EU/kg of endotoxin [202,203]. This threshold pyrogenic dose was established in clinical trials evaluating the safety and efficacy of systemically administered endotoxin for cancer therapy [204–207]. However, the threshold pyrogenic dose of endotoxin in the presence of mesoporous silica, titanium nanobelts, or any other nanomaterial capable of exaggerating the endotoxin-mediated inflammation is currently unknown.
Enhanced immunostimulatory activity of in silico discovered agonists of Toll-like receptor 2 (TLR2)
2017, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :In full accordance with this model, local or systemic administration of purified TLR ligands provokes potent anticancer activity in humans and mice. For example, LPS and flagellin, TLR4 and TLR5 ligands respectively, show effects against colorectal and lung cancer [9–12]. Imiquimod, which activates TLR7, is used in the therapy of skin cancer and chronic lymphocytic leukaemia [13].
The delicate balance of macrophages in colorectal cancer; their role in tumour development and therapeutic potential
2017, ImmunobiologyCitation Excerpt :The best known and one of the most potent activators of macrophages via Toll-like receptor (TLR) 4 is LPS, which originates from the outer membrane of gram-negative bacteria. The application of LPS in patients is, however, hindered by its toxicity and severe side effects, including hypotension, fever, disseminated blood clotting and lethal shock (de Bono et al., 2000; Engelhardt et al., 1991; Otto et al., 1996). Therefore, other microbial molecules like muramyl peptides – which are a group of peptidoglycans derived from the cell wall of gram-positive bacteria – have been investigated, as they have similar properties as LPS but less severe side effects (Hoedemakers et al., 1993).
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Present address: Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, U.K.