87. The use of the newly developed synthetic TLR-4 agonistas an immuno-therapeutic agent in a cancer model

Abstract

Glucopyranosyl lipid adjuvant (GLA) is a newly developed FDA-approved synthetic TLR-4 agonist, differing from LPS by having a defined number, length, and position of carbon chains, resulting in an efficient Th1 activation with minimal adverse Th2 effects. GLA is currently studied clinically as a vaccine-adjuvant, and here, for the first time, we examined its use in the field of cancer immunotherapy, employing the MADB106 mammary adenocarcinoma experimental metastasis model in F344 rats. GLA dose-dependently reduced lung tumor-retention (LTR) of intravenously injected MADB106 cells, and a single low dose of 2ug/rat, 24–48 h prior to tumor inoculation induced an up to 3-fold reduction in LTR, while causing minimal 1.5–2% body weight loss. A single GLA dose, three days before tumor inoculation, was more efficient than dividing it to two administrations, 48 h apart. Per dose, GLA was more effective in males than females, as reflected by greater LTR reduction (accompanied by higher body weight loss). Actual MADB106 metastases, numerated three weeks following inoculation, were reduced by 40% in both sexes after a single injection of GLA. NK cells mediated these beneficial effects, as they were absent in NK-depleted rats. Additionally, GLA administration elevated marginating lungs and liver NK cell cytotoxicity, but not circulating NK cytotoxicity. These results may bear implications for the clinical use of GLA in cancer therapy, and warrant further studies employing additional tumor models.