A Chemically Defined TLR3 Agonist with Anticancer Activity

Julie Le Naour, Sylvain Thierry, Sarah Adriana Scuderi, Mathilde Boucard-Jourdin, Peng Liu, Marc Bonnin, Yuhong Pan, Clémence Perret, Liwei Zhao, Misha Mao, Chloé Renoux, María Pérez-Lanzón, Baptiste Martin, Oliver Kepp, Guido Kroemer, Bettina Werlé

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    5 Citations (Scopus)

    Abstract

    Toll-like receptor 3 (TLR3) agonists such as polyinosinic:polycytidylic acid (poly(I:C)) have immunostimulatory effects that can be taken advantage of to induce anticancer immune responses in preclinical models. In addition, poly(I:C) has been introduced into clinical trials to demonstrate its efficacy as an adjuvant and to enhance the immunogenicity of locally injected tumors, thus reverting resistance to PD-L1 blockade in melanoma patients. Here, we report the pharmacokinetic, pharmacodynamic, mechanistic and toxicological profile of a novel TLR3 agonist, TL-532, a chemically synthesized double-stranded RNA that is composed by blocks of poly(I:C) and poly(A:U) (polyadenylic–polyuridylic acid). In preclinical models, we show that TL-532 is bioavailable after parenteral injection, has an acceptable toxicological profile, and stimulates the production of multiple chemokines and interleukins that constitute pharmacodynamic markers of its immunostimulatory action. When given at a high dose, TL-532 monotherapy reduced the growth of bladder cancers growing on mice. In addition, in immunodeficient mice lacking formylpeptide receptor-1 (FPR1), TL-532 was able to restore the response of orthotopic subcutaneous fibrosarcoma to immunogenic chemotherapy. Altogether, these findings may encourage further development of TL-532 as an immunotherapeutic anticancer agent.

    Original languageEnglish
    Article number2227510
    JournalOncoImmunology
    Volume12
    Issue number1
    DOIs
    Publication statusPublished - 1 Jan 2023

    Keywords

    • Cancer immunotherapy
    • dendritic cells
    • formyl peptide receptor 1
    • immmunogenic cell death

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