The defined TLR3 agonist, Nexavant, exhibits anti-cancer efficacy and potentiates anti-PD-1 antibody therapy by enhancing immune cell infiltration

Abstract

Nexavant has been reported as an alternative to the TLR3 agonist of Poly(I:C) and its derivatives. The physicochemical properties, signaling pathways, anti-cancer effects, and mechanisms of Nexavant were investigated. Nexavant’s distinct nature, compared to Poly(I:C), was evident through precise quantification, thermostability, and resistance to RNase A. Unlike Poly (I: C) which activates TLR3, RIG-I and MDA5, Nexavant stimulates the signaling through TLR3 and RIG-I but not MDA5. Intratumoral Nexavant treatment led to a unique immune response compared to Poly(I:C), immune cell infiltration, and suppression of tumor growth in various animal cancer models. Nexavant therapy outperformed anti-PD-1 antibody treatment in all tested models and showed a synergistic effect in combinational therapy, especially in well-defined cold tumor models. The effect was similar to Nivolumab in a humanized mouse model. Intranasal instillation of Nexavant recruited immune cells (NK, CD4+ T, CD8+ T) to the lungs, suppressing lung metastasis and improving animal survival. Our study highlighted Nexavant’s defined nature for clinical use, unique signaling pathways, and its potential as a standalone anti-cancer agent or in combination with anti-PD-1 antibody.Simple SummaryNexavant, a newly reported TLR3 agonist, has advantages over Poly(I:C) in quality control and pre-clinical efficacy. Here, we further investigated Nexavant’s physicochemical properties, downstream signaling pathways, anti-cancer efficacy, and mechanism of action. Nexavant was homogenous in solution, less sensitive to RNase A, and showed thermostability compared with Poly(I:C). Unlike Poly(I:C), the TLR3, RIGI, and MDA5 activator, Nexavant only activated TLR3 and RIG-I but not MDA5. Administration of Nexavant either by intratumoral or intranasal route suppressed tumor growth in various cancer models. Combination therapy with anti-PD-1 antibody exhibited synergistic tumor growth inhibition than the respective monotherapies. This study demonstrated that Nexavant could be more suitable for clinical use over Poly(I:C) and applied as an anti-cancer agent in the presence or absence of an anti-PD-1 antibody.