Perioperative treatment with the new synthetic TLR‐4 agonist GLA‐SE reduces cancer metastasis without adverse effects

Abstract

The use of TLR agonists as an anti-cancer treatment is gaining momentum given their capacity to activate various host cellular responses through the secretion of inflammatory cytokines and type-I interferons. It is now also recognized that the perioperative period is a window of opportunity for various interventions aiming at reducing the risk of cancer metastases – the major cause of cancer related death. However, immune-stimulatory approach has not been used perioperatively given several contraindications to surgery. To overcome these obstacles, in the current study we employed the newly introduced, fully synthetic TLR-4 agonist, Glucopyranosyl Lipid-A (GLA-SE), in various models of cancer metastases, and in the context of acute stress or surgery. Without exerting evident adverse effects, a single systemic administration of GLA-SE rapidly and dose dependently elevated both innate and adaptive immunity in the circulation, lungs, and the lymphatic system. Importantly, GLA-SE treatment led to reduced metastatic development of a mammary adenocarcinoma and a colon carcinoma by approximately 40-75% in F344 rats and BALB/c mice, respectively, at least partly through elevating marginating-pulmonary NK cell cytotoxicity. GLA-SE is safe and well tolerated in humans, and currently is used as an adjuvant in phase-II clinical trials. Given that the TLR-4 receptor and its signaling cascade is highly conserved throughout evolution, our current results suggest that GLA-SE may be a promising immune stimulatory agent in the context of oncological surgeries, aiming to reduce long-term cancer recurrence.

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

“…Activation of toll-like receptor signaling can lead to secretion of proinflammatory cytokines and type-I IFNs promoting adaptive and innate immune responses [106]. Glucopyranosyl Lipid-A is a recently generated synthetic TLR-4 agonist that is administered within a stable emulsion (GLA-SE) and specifically induces Th1 responses while minimizing Th2 responses [106].…”

“…Glucopyranosyl Lipid-A is a recently generated synthetic TLR-4 agonist that is administered within a stable emulsion (GLA-SE) and specifically induces Th1 responses while minimizing Th2 responses [106]. A Phase I/II clinical trial for treating MCC patients has completed enrollment and has been efficacious in some patients (NCT02035657) [107].…”

Stress impairs the efficacy of immune stimulation by CpG-C: Potential neuroendocrine mediating mechanisms and significance to tumor metastasis and the perioperative period

“…The drug was dissolved in a slow release vehicle (see below) and administered s.c. at a dose of 1.2 mg/kg [26]. …”

An Overview of Recombinant Vaccine Technology, Adjuvants and Vaccine Delivery Methods

“…Toll-like receptor (TLRs) agonists have been shown to be promising vaccine adjuvants in both preclinical and clinical studies, as they provide the opportunity to induce distinct cytokine profiles, thereby modulating and tailoring the vaccine-induced immune response [80]. New synthetic TLR agonists are being developed and their availability has expanded [81][82][83].…”