Details

Autor(en) / Beteiligte

• Matzner, Pini
• Sorski, Liat
• Shaashua, Lee
• Elbaz, Ely
• Lavon, Hagar
• Melamed, Rivka
• Rosenne, Ella
• Gotlieb, Neta
• Benbenishty, Amit
• Reed, Steve G.
• Ben‐Eliyahu, Shamgar

Titel

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

Ist Teil von

• International journal of cancer, 2016-04, Vol.138 (7), p.1754-1764

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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 this study, we used 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. What's new? The use of active chemotherapeutic regimens immediately prior to, during, or after surgery may significantly reduce the risk of metastatic development in cancer patients. Generally excluded from such perioperative regimens are immunostimulators, which tend to exhibit pro‐inflammatory activity. This study shows, however, that in rats and mice with mammary adenocarcinomas or colon carcinomas, respectively, the toll‐like receptor 4 agonist glucopyranosyl lipid‐A (GLA‐SE) is capable of reducing metastatic development by increasing host resistance to metastasis without exerting adverse effects. GLA‐SE, currently under study clinically for other conditions, may be an effective perioperative immunostimulator, lacking adverse effects and lowering the risk of cancer recurrence.