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Perioperative treatment with the new synthetic TLR ‐4 agonist GLA‐SE reduces cancer metastasis without adverse effects
Author(s) -
Matzner Pini,
Sorski Liat,
Shaashua Lee,
Elbaz Ely,
Lavon Hagar,
Melamed Rivka,
Rosenne Ella,
Gotlieb Neta,
Benbenishty Amit,
Reed Steve G.,
BenEliyahu Shamgar
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29885
Subject(s) - medicine , context (archaeology) , cancer , perioperative , agonist , immune system , metastasis , cancer research , immunology , receptor , biology , surgery , paleontology
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.