The understanding that the immune system can effectively fight cancer has prompted the exploration of diverse therapeutic modalities that either directly target cancer cells, innate immune cells or cells of the adaptive immune system. Agonists of the Toll like receptors 7/8 are appealing compounds for tumor-targeted cancer immuno-therapy owing to their potent intratumoral type I IFN signature, which is tightly linked to the induction of effective antitumor T cell immunity and a beneficial prognosis across multiple malignancies. Despite their potent TRL7/8 activation capacity, an important drawback of small molecule TLR7/8 agonists is their pharmacokinetic profile, as even local administration of these small molecules, lead to rapid systemic dissemination and provokes systemic inflammatory responses that lead to dose-limiting toxicity. Here we demonstrate that covalent conjugation of imidazoquinoline-based TLR7/8 agonists to pH-degradable colloids allows – contrary to IMDQ in soluble form – upon intratumoral administration in mice for localized immune-activation in the tumor microenvironment and in the tumor sentinel lymph nodes, while fully abrogating the systemic toxicity induced by soluble IMDQ. The strong reduction in tumor growth was found to be a consequence of lymphoid immune activation and the induction of tumor-specific T cell responses against tumor antigens. Importantly, the therapeutic efficacy could be further improved through synergism with immune checkpoint blockade.<br/>

Colloidal TLR7/8 agonist conjugated nanoparticles for safe and synergistic cancer immunotherapy

256th National Meeting (2018)

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