TLR3 agonists in the clinic
At the end of the 1970s a clinical immunotherapy trial using polyA/U in breast cancers was conducted at the Gustave Roussy Institute (Paris), showing increased survival among 300 women receiving this product intravenously (Lacour et al, The Lancet, 26 July 1980,161-164). These data were confirmed by another trial including 517 patients conducted between 1982 and 1985 (Lacour J et al, Breast cancer Res Treat 1991, Sep;19(1) 15-21).
A retrospective immunohistochemical analysis of 194 patients included in the latter trial in 2011 showed that the beneficial effect was directly attributable to the expression of TLR3 in the tumor (Salaun et al et al, Cancer Research, 2011, 71(5),1607-1614).
The heterogeneous structure of poly A/U and its poorly controlled mode of manufacturing made this product unusable for pharmaceutical purposes.
However, the highly promising results obtained and the good tolerance of the activation of TLR3 in humans led TOLLYS researchers to find new druggable molecules capable of reproducing the action of polyA/U.
This was achieved with a family of molecules including TL-532.
TLR3 agonists (dsRNA) are powerful activators of the innate immune system primarily antigen-presenting cells (dendritic cells and macrophages) (Alexopoulou et al., 2001). Activation of TLR3 also stimulates an inflammatory response in non-immune cells, such as epithelial and mesenchymal cells.
TOLLYS co-founders discovered that TLR3 agonists can trigger the apoptosis of epithelial cancer cells while sparing their normal counterparts (Salaun et al., 2006; Estornes et al., 2012).
TLR3 agonists induce immunogenic cell death of tumoral cells generating the release of apoptotic bodies displaying tumor antigens. In parallel, TLR3 agonists prime BDCA3+ Dendritic cells specialized in cross presentation to T cells. This leads to the activation of a large repertoire of CTL specific to the patient tumor antigens. TLR3 ligands also induce a switch of the tumor microenvironment by inducing the release of cytokines and chemiokines favorable to the activation and recruitment of CTL in the tumor bed. Altogether, TLR3 convert cold tumors into hot tumors with the activation and recruitment of an intense CTL response to destroy the tumor and induce auto-vaccination to prevent from recurrences.
Toll-like Receptor 3 (TLR3) was described in 2001 as a Pattern Recognition Receptor that binds to virus-derived, double-stranded RNA (dsRNA) and triggers the secretion of cytokines, including type I interferons.
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