Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence l'intérêt de nanoparticules délivrant des oligonucléotides CpG capables, en se liant au récepteur TLR9, de supprimer la croissance tumorale et d'améliorer l'efficacité d'inhibiteurs de point de contrôle immunitaire
Checkpoint inhibitor (CPI) immunotherapies have revolutionized the treatment of a wide array of cancers, but their utility remains limited to a subset of patients with favorable disease phenotypes. We show that the generation of peptide-based nanocomplexes carrying immunostimulatory oligonucleotides dramatically increases the potency of certain of these compounds to stimulate toll-like receptor signaling. The administration of immunostimulatory nanocomplexes carrying CpG oligonucleotides generates antitumor effects and enhances the efficacy of checkpoint inhibitor antibody therapy in mouse models of cancer, and the nanocomplex formulation enables drastic reductions in the dose required to generate therapeutic effects.The recent advent of immune checkpoint inhibitor (CPI) antibodies has revolutionized many aspects of cancer therapy, but the efficacy of these breakthrough therapeutics remains limited, as many patients fail to respond for reasons that still largely evade understanding. An array of studies in human patients and animal models has demonstrated that local signaling can generate strongly immunosuppressive microenvironments within tumors, and emerging evidence suggests that delivery of immunostimulatory molecules into tumors can have therapeutic effects. Nanoparticle formulations of these cargoes offer a promising way to maximize their delivery and to enhance the efficacy of checkpoint inhibitors. We developed a modular nanoparticle system capable of encapsulating an array of immunostimulatory oligonucleotides that, in some cases, greatly increase their potency to activate inflammatory signaling within immune cells in vitro. We hypothesized that these immunostimulatory nanoparticles could suppress tumor growth by activating similar signaling in vivo, and thereby also improve responsiveness to immune checkpoint inhibitor antibody therapies. We found that our engineered nanoparticles carrying a CpG DNA ligand of TLR9 can suppress tumor growth in several animal models of various cancers, resulting in an abscopal effect on distant tumors, and improving responsiveness to anti-CTLA4 treatment with combinatorial effects after intratumoral administration. Moreover, by incorporating tumor-homing peptides, immunostimulatory nucleotide-bearing nanoparticles facilitate antitumor efficacy after systemic intravenous (i.v.) administration.